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Chen L, Liu L, Lin T, Mai Z, Lu H, Hu B, Huang J, Ai H. HDAC9-Mediated Pyroptosis Promotes Orthodontically Induced Inflammatory Root Resorption. Int Dent J 2025; 75:1828-1842. [PMID: 40245750 DOI: 10.1016/j.identj.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 03/12/2025] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
INTRODUCTION AND AIMS Orthodontically induced inflammatory root resorption (OIIRR) is a common iatrogenic outcome of orthodontic treatment. Both epigenetic modifications and pyroptosis have demonstrated a certain role in OIIRR. This study aims to investigate whether epigenetic modifications regulate pyroptosis to be involved in OIIRR. METHOD Rat model of OIIRR was established, and the periodontal tissues were utilized for H&E staining, TRAP staining, immunofluorescence, transcriptome sequencing, and RT-qPCR analysis. Human periodontal ligament fibroblasts (hPDLFs) were overexpressed with HDAC9, treated with pyroptosis inhibitor, incubated with osteoclast, and then subjected to CUT&Tag sequencing. RESULTS Orthodontic force increased the distance of orthodontic tooth movement and the abundance of osteoclast. Transcriptome sequencing identified that Hdac9 was upregulated in the periodontal tissues of OIIRR rats compared to the control. Immunofluorescence revealed that HDAC9 was present in periodontal ligament fibroblasts, with reduced fluorescence of HDAC9 in OIIRR compared to the control. HDAC9 overexpression in hPDLFs induced pyroptosis and promoted osteoclast differentiation. These effects were reversed by pyroptosis inhibitor. CUT&Tag analysis showed that HDAC9 overexpression resulted in an enrichment of deacetylated genes on mitochondrial dysfunction-associated pathways. CUT&Tag-PCR analysis confirmed reduced H3K9ac enrichment on the mitochondrial dysfunction-associated genes VPS13D, AQP1, PEX2, CDK1, and PLEKHA1 after HDAC9 overexpression, and RT-qPCR analysis revealed a corresponding decrease in their respective expression levels. Accordingly, the ROS level was also increased by HDAC9 overexpression. CONCLUSION HDAC9-mediated histone deacetylation induces mitochondrial dysfunction and pyroptosis in hPDLFs, thereby promoting osteoclast differentiation and OIIRR progression. CLINICAL RELEVANCE This study reveals the regulatory mechanism of pyroptosis in OIIRR from the perspective of epigenetic modifications, providing new insights into the pathogenesis of OIIRR.
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Affiliation(s)
- Lin Chen
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Limin Liu
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Tianwei Lin
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhihui Mai
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hongfei Lu
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bingxue Hu
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junhao Huang
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hong Ai
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Suamphan S, Makeudom A, Krisanaprakornkit S, Meekhantong P, Dechtham E, Leethanakul C. Enhanced osteogenic differentiation of human periodontal ligament cells by mature osteoclasts. J Oral Biosci 2025; 67:100632. [PMID: 39993474 DOI: 10.1016/j.job.2025.100632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 02/26/2025]
Abstract
OBJECTIVE Several in vitro studies have shown that reverse signaling from osteoclasts regulates osteoblast differentiation and mineralization. However, none of these studies have reported the effects of this signaling pathway on periodontal ligament (PDL) cells. Therefore, in this study, we aimed to investigate the interaction between receptor activators of nuclear factor kappa B (RANK) released from mature human osteoclasts and the membranous RANK ligand (RANKL) in human PDL cells. METHODS Multinucleated mature human osteoclasts were differentiated from peripheral blood mononuclear cells upon incubation with recombinant macrophage colony-stimulating factor and RANKL. Mature osteoclasts and human PDL cells were characterized. A mature osteoclast-conditioned medium (OC-CM) was used to induce osteogenic differentiation of PDL cells. Mechanistic analysis of RANK-RANKL reverse signaling were conducted to determine the regulation of osteogenic induction using conditioned medium from mature osteoclasts treated with GW4869 (GW-OC-CM) or PDL cells pretreated with recombinant human osteoprotegerin (OPG). RESULTS OC-CM significantly upregulated the mRNA expression of osteogenic genes and enhanced the osteogenic differentiation and biomineralization of PDL cells (p < 0.05). GW-OC-CM significantly reduced the expression of osteogenic genes, osteogenic differentiation, and biomineralization in PDL cells (p < 0.05). Similarly, the pretreatment of PDL cells with OPG before OC-CM treatment significantly reduced the osteogenic induction of PDL cells (p < 0.05). CONCLUSION Mature osteoclasts can induce osteogenesis in human PDL cells via RANK-RANKL reverse signaling.
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Affiliation(s)
- Sumit Suamphan
- Orthodontic Section, Department of Preventive Dentistry, Faculty of Dentistry, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
| | - Anupong Makeudom
- School of Dentistry, Mae Fah Luang University, Chiang Rai 57100, Thailand
| | | | | | - Ekapong Dechtham
- School of Dentistry, Mae Fah Luang University, Chiang Rai 57100, Thailand
| | - Chidchanok Leethanakul
- Orthodontic Section, Department of Preventive Dentistry, Faculty of Dentistry, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand; Center of Excellence for Oral Health, Faculty of Dentistry, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
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Minato Y, Aoki-Nonaka Y, Lwin HY, Ando D, Warita Y, Matsugishi-Nasu A, Hiyoshi T, Takahashi N, Tabeta K. Allyl isothiocyanate suppressed periodontal tissue destruction in mice via bacteriostatic and anti-inflammatory activities against Porphyromonas gingivalis. Arch Oral Biol 2025; 169:106118. [PMID: 39486276 DOI: 10.1016/j.archoralbio.2024.106118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 10/18/2024] [Accepted: 10/20/2024] [Indexed: 11/04/2024]
Abstract
OBJECTIVES Allyl isothiocyanate (AITC) is a phytochemical that is abundantly present in cruciferous vegetables, such as wasabi and mustard. Among its pharmacological properties, it demonstrates anticancer, antifungal, and anti-inflammatory activities. This study aimed to investigate the functions of AITC against periodontopathic bacteria and its effects on a mouse model of periodontitis. DESIGN The antimicrobial and antibiofilm functions of AITC were assessed against Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus mitis. To clarify its anti-inflammatory effects, macrophage-like cells from THP-1 were stimulated with P. gingivalis lipopolysaccharide (LPS), and the release of inflammatory cytokines was analyzed by ELISA. Experimental periodontitis was induced in 9-week-old mice by ligation and oral infection of P. gingivalis, and AITC was injected into the gingiva once daily for 8 days. Alveolar bone resorption was evaluated by measuring the exposed root area. Gene expressions in the periodontal tissue were analyzed via qPCR. RESULTS AITC exerted weak bacteriostatic effects against P. gingivalis, inhibiting biofilm formation. AITC also impeded the production of interleukin-6 and tumor necrosis factor-α induced by P. gingivalis LPS. Additionally, transient receptor potential ankyrin 1(TRPA1) channel agonist inhibited the anti-inflammatory effects of AITC. In vivo, AITC inhibited alveolar bone destruction and decreased the gene transcription of Il6 in the periodontal tissue. CONCLUSION AITC exerted weak bacteriostatic and anti-inflammatory effects against P. gingivalis, reducing alveolar bone destruction and suppressing the inflammatory response in experimental periodontitis. Therefore, AITC may serve as a valuable adjunct in controlling periodontal disease.
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Affiliation(s)
- Yukako Minato
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yukari Aoki-Nonaka
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Hnin Yu Lwin
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Daiki Ando
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuko Warita
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Aoi Matsugishi-Nasu
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takumi Hiyoshi
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Naoki Takahashi
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Koichi Tabeta
- Division of Periodontology, Niigata University Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata, Japan.
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Huang Y, Tang Y, Zhang R, Wu X, Yan L, Chen X, Wu Q, Chen Y, Lv Y, Su Y. Role of periodontal ligament fibroblasts in periodontitis: pathological mechanisms and therapeutic potential. J Transl Med 2024; 22:1136. [PMID: 39709490 PMCID: PMC11663348 DOI: 10.1186/s12967-024-05944-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 12/05/2024] [Indexed: 12/23/2024] Open
Abstract
Periodontal ligament fibroblasts (PDLFs) play a crucial role in the etiology of periodontitis and periodontal tissue regeneration. In healthy periodontal tissues, PDLFs maintain the homeostasis of periodontal soft and hard tissues as well as the local immune microenvironment. PDLFs also have the potential for multidirectional transdifferentiation and are involved in periodontal tissue regeneration. On the other hand, PDLFs can become dysfunctional and acquire an inflammatory phenotype to secret various inflammatory cytokines when affected by pathological factors. These cytokines further trigger immune and inflammatory events, and lead to destruction of periodontal soft and hard tissues as well as damage to the regenerative potential of PDLFs. This review summarizes the physiological functions of PDLFs. Meanwhile, this review also highlights recent insights into the pathological mechanisms driving the development of periodontitis through dysfunctional PDLFs and the negative impact on periodontal tissue regeneration. Additionally, this paper summarizes strategies for targeting PDLFs to treat periodontitis, involving blocking multiple stages of the inflammatory response induced by PDLFs and promoting the multidirectional transdifferentiation of PDLFs. Future research directions are proposed to address important questions that have not yet been answered in this field. This article provides a reference for understanding the important role of PDLFs in the pathological mechanisms of periodontitis and for developing new strategies for targeting PDLFs in periodontitis treatment.
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Affiliation(s)
- Yijie Huang
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Ying Tang
- Department of Prosthodontics, Huangpu District Dental Disease Prevention and Treatment Institute, Shanghai, 200001, China
| | - Ruiqi Zhang
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Xiao Wu
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Li Yan
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Xiling Chen
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Qianqi Wu
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Yiyan Chen
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Yingtao Lv
- Department of Prosthodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Su
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
- Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, China.
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Hadagalu Revana Siddappa R, Bishop E, Ali A, Magalhaes M, Kishen A. Engineered Immunomodulatory Nanoparticles Inhibit Root Resorption and Ankylosis. J Endod 2024; 50:1579-1592.e3. [PMID: 39159870 DOI: 10.1016/j.joen.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 08/21/2024]
Abstract
INTRODUCTION External root resorption following avulsion injury is a complex process wherein differentiation of macrophages (Mϕ) to multinucleated osteoclasts is temporally regulated by resident periodontal fibroblasts (PDLF). The current study aims to assess the effect of engineered bioactive chitosan nanoparticles (CSNP), sustained released dexamethasone conjugated CSNP (CS-DEX) and CSNP functionalized with photosensitizer Rose Bengal (CSRB) for application in root resorption using an in-vitro PDLF-Mϕ direct coculture model and in-vivo delayed reimplantation model. METHODS PDLF-Mϕ direct coculture system was exposed to lipopolysaccharide (LPS), macrophage colony stimulating factor, receptor activator of nuclear factor kappa β ligand with or without CSNP/CS-DEX for 7 days. Clastic differentiation was assessed by tartrate resistant acid phosphatase (TRAP) staining on day 7. On day 2 and 7, immunofluorescence analysis was conducted to assess the expression of Mϕ polarization markers (CD80, CD206), multinucleation markers (NFATc1, STAT6) in Mϕ and matricellular protein periostin in PDLF and cytokine profiling in cell culture supernatants. Delayed replantation model with extraoral air dry/LPS exposure for 1h followed by root surface treatment with CS-DEX/CSRB was used in Wistar rats. After 21 days, rats were euthanized for histologic and immunofluorescence analysis. Statistical analysis one-way ANOVA with Tukey's multiple comparisons was used to analyze the data (P < .05). RESULTS CS-DEX significantly reduced TRAP+ multinucleated cells and CSNP treatment showed no TRAP+ cells. Immunofluorescence analysis showed that CSNP/CS-DEX reduced CD80, NFATc1 and STAT6 expression and increased periostin as expressed by fluorescence intensity. CSNP/CS-DEX significantly reduced TNFα, MMP9 and increased IL10, TGFβ1. Osteoprotegerin was upregulated only by CSNP. Root surface treatment in delayed replantation model showed that CS-DEX and CSRB substantially reduced the degree of resorption and ankylosis. Further, CD80, CD206, and MMP2 expression in groups with root surface treatment with CS-DEX and CSRB was lower than airdry/LPS group and similar to healthy control and NFATc1, STAT6, and MMP9 expressions were lower than healthy control. CONCLUSION The engineered nanosized immunomodulatory bioactive materials chitosan nanoparticles functionalized with photosensitizer and dexamethasone effectively reduced the clastic differentiation of Mϕ in in-vitro coculture and minimized the resorption and ankylosis in a delayed reimplantation model. These biomaterials have the potential to serve as root modification agents, promoting favorable healing outcomes in cases of dental avulsion.
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Affiliation(s)
| | - Emily Bishop
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, Canada; Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - Aiman Ali
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, Canada; Oral and Maxillofacial Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Marco Magalhaes
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, Canada
| | - Anil Kishen
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, Canada; Faculty of Dentistry, University of Toronto, Toronto, Canada; Department of Dentistry, Mount Sinai Health System, Mount Sinai Hospital, Toronto, Canada.
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Rajeshwari HRS, Bishop E, Ali A, Kishen A. Deciphering 3D periodontal fibroblast-macrophage crosstalk in bioactive nanoparticle-guided immunomodulation for treating traumatic dental avulsion. Bioact Mater 2024; 41:400-412. [PMID: 39184829 PMCID: PMC11342124 DOI: 10.1016/j.bioactmat.2024.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 07/09/2024] [Accepted: 07/13/2024] [Indexed: 08/27/2024] Open
Abstract
Prolonged extra-oral period in dental avulsion is often associated with loss of viability of Periodontal fibroblasts (PDLF) and increased risk of ankylosis. Root surface treatment with bioactive agents to reduce the risk of ankylosis can be a potential strategy. The objective of the study was to investigate the impact of an engineered chitosan nanoparticles (CSNP), photosensitizer Rose Bengal (RB) functionalized CSNP (CSRB) and sustained dexamethasone (CSDEX) releasing CSNP for application in management of delayed replantation of avulsed teeth. The 3D PDLF-macrophage (Mϕ) collagen model was developed and exposed to LPS, MCSF, RANKL with and without CSDEX/CSNP. Immunofluorescence and cytokine analysis was done at 2 and 7 days to assess cellular interactions. Maxillary right incisors in male Wistar rats were extracted, exposed to extraoral dry or LPS for 1 h and treated with or without CSDEX/CSRB for 1 min before replantation. Rats were euthanized after 21 days for micro-CT, TRAP, and immunofluorescence analysis. CSDEX/CSNP treatment in 3D model significantly reduced CD80, NFATc1, STAT6 and increased CD206 and periostin expression (p < 0.05). TNFα, MMP9 was downregulated and IL10, TGFβ1, MMP2 upregulated with CSDEX/CSNP (p < 0.05). CSDEX/CSRB in animal study significantly reduced resorption, ankylosis, TRAP activity and osteocalcin expression and increased periostin (p<0.05). CSDEX demonstrated higher anti-inflammatory activity by downregulating TNFα, while CSNP upregulated TGFβ1, periostin, and downregulated MMP9. The combination of matrix stabilization with CSRB with periostin upregulation and sustained releasing CSDEX showed potential for hampering root resorption and ankylosis in dental avulsion.
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Affiliation(s)
| | - Emily Bishop
- Faculty of Dentistry, University of Toronto, Toronto, ON, M5G 1G6, Canada
| | - Aiman Ali
- Oral and Maxillofacial Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ontario M5G 1G6, Canada
| | - Anil Kishen
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, ON, M5G 1G6, Canada
- Faculty of Dentistry, University of Toronto, Toronto, ON, M5G 1G6, Canada
- Department of Dentistry, Mount Sinai Health System, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
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Peng B, Wang L, Han G, Cheng Y. Mesenchymal stem cell-derived exosomes: a potential cell-free therapy for orthodontic tooth stability management. Stem Cell Res Ther 2024; 15:342. [PMID: 39354604 PMCID: PMC11446149 DOI: 10.1186/s13287-024-03962-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 09/25/2024] [Indexed: 10/03/2024] Open
Abstract
Orthodontic relapse (OR) occurs at a rate of over 70%. Retention is the current attempt at prevention, but it requires a considerable amount of time and cannot fully block OR. It's imperative to find a safe and effective method for managing post-orthodontic tooth stability. Periodontal bone remodeling is one crucial biological foundation of OR. Mesenchymal stem cell-derived exosomes (MSC-Exo) show promise in relapse management by regulating periodontal bone remodeling. MSC-Exo can prevent relapse by regulating periodontal ligament function, osteoclast activity, osteoblast differentiation, macrophage polarization, and periodontal microcirculation. In recent years, exosome-loaded hydrogels, which achieve controlled exosome release, have demonstrated efficacy in promoting bone regeneration and remodeling, offering promising prospects for OR management. This review aims to highlight the use of MSC-Exo-based therapy for preventing OR, offering new insights for future research focused on improving tooth stability and enhancing orthodontic anchorage.
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Affiliation(s)
- Boyuan Peng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China
| | - Lianhao Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China
| | - Guangli Han
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China.
- Department of Orthodontics Division II, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
| | - Yong Cheng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China.
- Department of Oral Radiology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
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Zhang Y, Shi H. Ginsenoside Rb3 alleviates the formation of osteoclasts induced by periodontal ligament fibroblasts in the periodontitis microenvironment through the STAT3 pathway. Cell Biol Int 2024; 48:1343-1353. [PMID: 38934258 DOI: 10.1002/cbin.12201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 05/14/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024]
Abstract
This study explores the potential role and mechanism of Ginsenoside Rb3 (Rb3) in modulating osteoclastogenesis induced by human periodontal ligament fibroblasts (hPLFs) within the periodontitis microenvironment. We investigated the anti-inflammatory effects of Rb3 on hPLFs stimulated with Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) utilizing quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay techniques. Moreover, the functional role of Rb3 in hPLFs-induced osteoclast formation was assessed by treating human bone marrow-derived macrophages (hBMMs) with conditioned medium from hPLFs, followed by analyses through qPCR, western blot analysis, and staining for tartrate-resistant acid phosphatase (TRAP) and phalloidin. The impact of Rb3 on the activation of the STAT3 signaling pathway was determined via western blot analysis. Results indicated that Rb3 treatment significantly suppressed the upregulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1, and IL-18) at both gene and protein levels in hPLFs induced by P.g-LPS. Furthermore, conditioned medium from Rb3 plus P.g-LPS treated hPLFs notably decreased the number of TRAP-positive cells, actin ring formations, and the expression of osteoclast marker genes (including CTSK, NFATC1, and ACP5). Rb3 also inhibited the P.g-LPS-induced activation of the STAT3 pathway, with the activation of STAT3 partially reversing the effects of Rb3 on inflammation and osteoclast differentiation. Collectively, Rb3 ameliorates inflammation in P.g-LPS-stimulated hPLFs and reduces hPLFs-induced osteoclastogenesis by inhibiting the STAT3 signaling pathway, suggesting its potential as a therapeutic agent for periodontitis.
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Affiliation(s)
- Yuhua Zhang
- Department of Stomatology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hanping Shi
- Department of Stomatology, Fujian Medical University Union Hospital, Fuzhou, China
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Prins CM, Ceylan M, Hogervorst JMA, Jansen IDC, Schimmel IM, Schoenmaker T, de Vries TJ. Osteogenic differentiation of periodontal ligament fibroblasts inhibits osteoclast formation. Eur J Cell Biol 2024; 103:151440. [PMID: 38954934 DOI: 10.1016/j.ejcb.2024.151440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/02/2024] [Accepted: 06/27/2024] [Indexed: 07/04/2024] Open
Abstract
One of the deficits of knowledge on bone remodelling, is to what extent cells that are driven towards osteogenic differentiation can contribute to osteoclast formation. The periodontal ligament fibroblast (PdLFs) is an ideal model to study this, since they play a role in osteogenesis, and can also orchestrate osteoclastogenesis.when co-cultured with a source of osteoclast-precursor such as peripheral blood mononuclear cells (PBMCs). Here, the osteogenic differentiation of PdLFs and the effects of this process on the formation of osteoclasts were investigated. PdLFs were obtained from extracted teeth and exposed to osteogenic medium for 0, 7, 14, or 21 out of 21 days. After this 21-day culturing period, the cells were co-cultured with peripheral blood mononuclear cells (PBMCs) for an additional 21 days to study osteoclast formation. Alkaline phosphatase (ALP) activity, calcium concentration, and gene expression of osteogenic markers were assessed at day 21 to evaluate the different stages of osteogenic differentiation. Alizarin red staining and scanning electron microscopy were used to visualise mineralisation. Tartrate-resistant acid phosphatase (TRAcP) activity, TRAcP staining, multinuclearity, the expression of osteoclastogenesis-related genes, and TNF-α and IL-1β protein levels were assessed to evaluate osteoclastogenesis. The osteogenesis assays revealed that PdLFs became more differentiated as they were exposed to osteogenic medium for a longer period of time. Mineralisation by these osteogenic cells increased with the progression of differentiation. Culturing PdLFs in osteogenic medium before co-culturing them with PMBCs led to a significant decrease in osteoclast formation. qPCR revealed significantly lower DCSTAMP expression in cultures that had been supplemented with osteogenic medium. Protein levels of osteoclastogenesis stimulator TNF-α were also lower in these cultures. The present study shows that the osteogenic differentiation of PdLFs reduces the osteoclastogenic potential of these cells. Immature cells of the osteoblastic lineage may facilitate osteoclastogenesis, whereas mature mineralising cells may suppress the formation of osteoclasts. Therefore, mature and immature osteogenic cells may have different roles in maintaining bone homeostasis.
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Affiliation(s)
- Caya M Prins
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands; Amsterdam University College (University of Amsterdam and Vrije Universiteit), Amsterdam, the Netherlands
| | - Merve Ceylan
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands
| | - Jolanda M A Hogervorst
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands
| | - Ineke D C Jansen
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands
| | - Irene M Schimmel
- Department of Medical Biology, Amsterdam University Medical Centre, Amsterdam, the Netherlands
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands
| | - Teun J de Vries
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands.
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Ceylan M, Schoenmaker T, Hogervorst JMA, Jansen IDC, Schimmel IM, Prins CM, Laine ML, de Vries TJ. Osteogenic Differentiation of Human Gingival Fibroblasts Inhibits Osteoclast Formation. Cells 2024; 13:1090. [PMID: 38994943 PMCID: PMC11240541 DOI: 10.3390/cells13131090] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/13/2024] Open
Abstract
Gingival fibroblasts (GFs) can differentiate into osteoblast-like cells and induce osteoclast precursors to differentiate into osteoclasts. As it is unclear whether these two processes influence each other, we investigated how osteogenic differentiation of GFs affects their osteoclast-inducing capacity. To establish step-wise mineralization, GFs were cultured in four groups for 3 weeks, without or with osteogenic medium for the final 1, 2, or all 3 weeks. The mineralization was assessed by ALP activity, calcium concentration, scanning electron microscopy (SEM), Alizarin Red staining, and quantitative PCR (qPCR). To induce osteoclast differentiation, these cultures were then co-cultured for a further 3 weeks with peripheral blood mononuclear cells (PBMCs) containing osteoclast precursors. Osteoclast formation was assessed at different timepoints with qPCR, enzyme-linked immunosorbent assay (ELISA), TRAcP activity, and staining. ALP activity and calcium concentration increased significantly over time. As confirmed with the Alizarin Red staining, SEM images showed that the mineralization process occurred over time. Osteoclast numbers decreased in the GF cultures that had undergone osteogenesis. TNF-α secretion, a costimulatory molecule for osteoclast differentiation, was highest in the control group. GFs can differentiate into osteoblast-like cells and their degree of differentiation reduces their osteoclast-inducing capacity, indicating that, with appropriate stimulation, GFs could be used in regenerative periodontal treatments.
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Affiliation(s)
- Merve Ceylan
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Jolanda M. A. Hogervorst
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Ineke D. C. Jansen
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Irene M. Schimmel
- Department of Medical Biology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Caya M. Prins
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Marja L. Laine
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Teun J. de Vries
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
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11
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Sun S, Yan T, Yang N, Wu J, Liu Z. Regulation of osteoclast differentiation and inflammatory signaling by TCF8 in periodontitis. Oral Dis 2024; 30:2580-2591. [PMID: 37246926 DOI: 10.1111/odi.14623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 04/19/2023] [Accepted: 05/17/2023] [Indexed: 05/30/2023]
Abstract
OBJECTIVES The aim of this study was to explore the potential role of zinc-finger homeodomain transcription factor (TCF8) in osteoclastogenesis and inflammation during periodontitis. MATERIALS AND METHODS Rats with periodontitis were induced via Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) injection. The recombinant lentivirus delivering short hairpin RNA (shRNA) against TCF8 was used to downregulate TCF8 in vivo. Alveolar bone loss in rats was determined by micro-computed tomography (Micro-CT). Typical pathological changes, periodontal tissue inflammation, and osteoclastogenesis were evaluated via histological analyses. The RAW264.7-derived osteoclasts were induced by RANKL stimulation. TCF8 downregulation in vitro was achieved by lentivirus infection. The osteoclast differentiation and inflammatory signaling in RANKL-induced cells were measured via immunofluorescence methods and molecular biology approaches. RESULTS Porphyromonas gingivalis-lipopolysaccharide induced rats exhibited overexpressed TCF8 in their periodontal tissues, while TCF8 knockdown attenuated the bone loss, tissue inflammation, and osteoclastogenesis in LPS-induced rats. Besides, TCF8 silencing inhibited RANKL-induced osteoclast differentiation in RAW264.7 cells, as evidenced by the reduced numbers of TRAP-positive osteoclasts, less formation of F-actin rings, and downregulated expressions of osteoclast-specific markers. It also exerted an inhibitory effect on the NF-κB signaling in RANKL-induced cells via blocking NF-κB p65 phosphorylation and nuclear translocation. CONCLUSIONS TCF8 silencing inhibited alveolar bone loss, osteoclast differentiation, and inflammation in periodontitis.
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Affiliation(s)
- Shiqun Sun
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Tongtong Yan
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Nan Yang
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Jian Wu
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Zhihui Liu
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
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12
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Mo S, Jang JS, Lee SH, Kim HH. Single-cell transcriptome analysis reveals periodontal ligament fibroblast heterogeneity with distinct IL-1β and RANKL expression in periodontitis. Mol Cells 2024; 47:100059. [PMID: 38554844 PMCID: PMC11026731 DOI: 10.1016/j.mocell.2024.100059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/26/2024] [Accepted: 03/26/2024] [Indexed: 04/02/2024] Open
Abstract
Periodontitis (PD) is an inflammatory disease with alveolar bone destruction by osteoclasts (OCs). In PD, both inflammation and OC activation are significantly influenced by periodontal ligament fibroblasts (PDL-Fib). Yet, whether PDL-Fib has heterogeneity and whether distinct PDL-Fib subsets have specific functions have not been investigated. In this study, we discovered the complexity of PDL-Fib in PD, utilizing single-cell RNA sequencing data from human PD patients. We identified distinct subpopulations of PDL-Fib: one expressing interleukin-1 beta (IL-1β) and another expressing the receptor activator of nuclear factor-kappa B ligand (RANKL), both crucial in OC differentiation and bone resorption. In periodontal tissues of mice with PD, active IL-1β, cleaved caspase 1, and nucleotide-binding oligomerization domain-like receptor 3 (NLPR3) were significantly elevated, implicating the NLRP3 inflammasome in IL-1β production. Upon stimulation of PDL-Fib with LPS from Porphyromonas gingivalis (pg), the most well-characterized periodontal bacteria, a more rapid increase in IL-1β, followed by RANKL induction, was observed. IL-1β and tumor necrosis factor alpha (TNF-α), another LPS-responsive cytokine, effectively increased RANKL in PDL-Fib, suggesting an indirect effect of pgLPS through IL-1β and TNF-α on RANKL induction. Immunohistological analyses of mouse periodontal tissues also showed markedly elevated levels of IL-1β and RANKL upon PD induction and displayed separate locations of IL-1β-expressing PDL-Fib and RANKL-expressing PDL-Fib in PD. The heterogenic feature of fibroblasts expressing IL-1β and RANKL was also mirrored in our combined cross-tissue single-cell RNA sequencing datasets analysis. In summary, our study elucidates the heterogeneity of PDL-Fib, highlighting distinct functional groups for producing RANKL and IL-1β, which collectively promote OC generation and bone destruction in PD.
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Affiliation(s)
- Shenzheng Mo
- Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 03080, Korea
| | - Ji Sun Jang
- Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 03080, Korea
| | - Seung Hye Lee
- Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 03080, Korea
| | - Hong-Hee Kim
- Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 03080, Korea.
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13
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Xie L, Ren X, Yang Z, Zhou T, Zhang M, An W, Guan Z. Exosomal circ_0000722 derived from periodontal ligament stem cells undergoing osteogenic differentiation promotes osteoclastogenesis. Int Immunopharmacol 2024; 128:111520. [PMID: 38199194 DOI: 10.1016/j.intimp.2024.111520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 01/05/2024] [Accepted: 01/05/2024] [Indexed: 01/12/2024]
Abstract
Periodontal ligament stem cells (PDLSCs), which are considered promising stem cells for regeneration of periodontal bony tissue, can also manipulate alveolar bone remodeling by exosomes. In this study, we investigated interactions between PDLSCs under osteogenic differentiation and osteoclast precursors. The results showed that conditioned medium from PDLSCs under 5d osteogenic induction promoted osteoclastogenesis of RAW264.7 cells. The exosomes extracted from those conditioned media showed similar effects on osteoclastogenesis. Furthermore, exosomes from PDLSCs under 5d of osteogenic induction showed significantly high expression of circ_0000722, compared with exosomes from PDLSCs before osteogenic induction. Downregulation of circ_0000722 significantly attenuated the effect of PDLSC-derived exosomes on the osteoclastogenesis of RAW264.7 cells. Our findings suggested that exosomal circ_0000722 derived from periodontal ligament stem cells undergoing osteogenic differentiation might promote osteoclastogenesis by upregulating TRAF6 expression and activating downstream NF-κB and AKT signaling pathways.
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Affiliation(s)
- Liangkun Xie
- Department of Oral Implantology, Kunming Medical University School and Hospital of Stomatology, Kunming, Yunnan, China; Yunnan Key Laboratory of Stomatology, Kunming, Yunnan, China
| | - Xuefeng Ren
- Yunnan Key Laboratory of Stomatology, Kunming, Yunnan, China; Department of Periodontology, Kunming Medical University School and Hospital of Stomatology, Kunming, Yunnan, China
| | - Zijie Yang
- Department of Oral Implantology, Kunming Medical University School and Hospital of Stomatology, Kunming, Yunnan, China; Yunnan Key Laboratory of Stomatology, Kunming, Yunnan, China
| | - Ting Zhou
- Yunnan Key Laboratory of Stomatology, Kunming, Yunnan, China
| | - Mingzhu Zhang
- Yunnan Key Laboratory of Stomatology, Kunming, Yunnan, China; Department of Periodontology, Kunming Medical University School and Hospital of Stomatology, Kunming, Yunnan, China
| | - Wei An
- Department of Oral Implantology, Kunming Medical University School and Hospital of Stomatology, Kunming, Yunnan, China; Yunnan Key Laboratory of Stomatology, Kunming, Yunnan, China
| | - Zheng Guan
- Biomedical Research Center, the Affiliated Calmette Hospital of Kunming Medical University (the First Hospital of Kunming), Kunming, Yunnan, China.
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14
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Wang W, Wang Q, Sun S, Zhang P, Li Y, Lin W, Li Q, Zhang X, Ma Z, Lu H. CD97 inhibits osteoclast differentiation via Rap1a/ERK pathway under compression. Int J Oral Sci 2024; 16:12. [PMID: 38311610 PMCID: PMC10838930 DOI: 10.1038/s41368-023-00272-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/24/2023] [Accepted: 12/24/2023] [Indexed: 02/06/2024] Open
Abstract
Acceleration of tooth movement during orthodontic treatment is challenging, with osteoclast-mediated bone resorption on the compressive side being the rate-limiting step. Recent studies have demonstrated that mechanoreceptors on the surface of monocytes/macrophages, especially adhesion G protein-coupled receptors (aGPCRs), play important roles in force sensing. However, its role in the regulation of osteoclast differentiation remains unclear. Herein, through single-cell analysis, we revealed that CD97, a novel mechanosensitive aGPCR, was expressed in macrophages. Compression upregulated CD97 expression and inhibited osteoclast differentiation; while knockdown of CD97 partially rescued osteoclast differentiation. It suggests that CD97 may be an important mechanosensitive receptor during osteoclast differentiation. RNA sequencing analysis showed that the Rap1a/ERK signalling pathway mediates the effects of CD97 on osteoclast differentiation under compression. Consistently, we clarified that administration of the Rap1a inhibitor GGTI298 increased osteoclast activity, thereby accelerating tooth movement. In conclusion, our results indicate that CD97 suppresses osteoclast differentiation through the Rap1a/ERK signalling pathway under orthodontic compressive force.
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Affiliation(s)
- Wen Wang
- Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, Hebei Medical University, Shijiazhuang, China
- Department of Orthodontics, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Qian Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shiying Sun
- Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, Hebei Medical University, Shijiazhuang, China
- Department of Orthodontics, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Pengfei Zhang
- Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, Hebei Medical University, Shijiazhuang, China
- Department of Orthodontics, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Yuyu Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Weimin Lin
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qiwen Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiao Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhe Ma
- Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, Hebei Medical University, Shijiazhuang, China.
- Department of Preventive Dentistry, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, Hebei, China.
| | - Haiyan Lu
- Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, Hebei Medical University, Shijiazhuang, China.
- Department of Orthodontics, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China.
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15
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Pascoal S, Oliveira S, Monteiro F, Padrão J, Costa R, Zille A, Catarino SO, Silva FS, Pinho T, Carvalho Ó. Influence of Ultrasound Stimulation on the Viability, Proliferation and Protein Expression of Osteoblasts and Periodontal Ligament Fibroblasts. Biomedicines 2024; 12:361. [PMID: 38397963 PMCID: PMC10886604 DOI: 10.3390/biomedicines12020361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Among the adjunctive procedures to accelerate orthodontic tooth movement (OTM), ultrasound (US) is a nonsurgical form of mechanical stimulus that has been explored as an alternative to the currently available treatments. This study aimed to clarify the role of US in OTM by exploring different stimulation parameters and their effects on the biological responses of cells involved in OTM. Human fetal osteoblasts and periodontal ligament fibroblasts cell lines were stimulated with US at 1.0 and 1.5 MHz central frequencies and power densities of 30 and 60 mW/cm2 in continuous mode for 5 and 10 min. Cellular proliferation, metabolic activity and protein expression were analyzed. The US parameters that significantly improved the metabolic activity were 1.0 MHz at 30 mW/cm2 for 5 min and 1.0 MHz at 60 mW/cm2 for 5 and 10 min for osteoblasts; and 1.0 MHz at 30 mW/cm2 for 5 min and 1.5 MHz at 60 mW/cm2 for 5 and 10 min for fibroblasts. By stimulating with these parameters, the expression of alkaline phosphatase was maintained, while osteoprotegerin synthesis was induced after three days of US stimulation. The US stimulation improved the biological activity of both osteoblasts and periodontal ligament fibroblasts, inducing their osteogenic differentiation.
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Affiliation(s)
- Selma Pascoal
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal; (S.P.)
- Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azurém, 4800-058 Guimarães, Portugal (S.O.C.); (Ó.C.)
| | - Sofia Oliveira
- Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azurém, 4800-058 Guimarães, Portugal (S.O.C.); (Ó.C.)
| | - Francisca Monteiro
- Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azurém, 4800-058 Guimarães, Portugal (S.O.C.); (Ó.C.)
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Jorge Padrão
- Center for Textile Science and Technology (2C2T), Department of Textile Engineering, University of Minho, Campus of Azurém, 4800-058 Guimarães, Portugal; (J.P.); (A.Z.)
| | - Rita Costa
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal; (S.P.)
| | - Andrea Zille
- Center for Textile Science and Technology (2C2T), Department of Textile Engineering, University of Minho, Campus of Azurém, 4800-058 Guimarães, Portugal; (J.P.); (A.Z.)
| | - Susana O. Catarino
- Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azurém, 4800-058 Guimarães, Portugal (S.O.C.); (Ó.C.)
- LABBELS—Associate Laboratory, 4710-057 Braga, Portugal
| | - Filipe S. Silva
- Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azurém, 4800-058 Guimarães, Portugal (S.O.C.); (Ó.C.)
- LABBELS—Associate Laboratory, 4710-057 Braga, Portugal
| | - Teresa Pinho
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal; (S.P.)
- IBMC—Instituto Biologia Molecular e Celular, i3S—Inst. Inovação e Investigação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
| | - Óscar Carvalho
- Center for MicroElectroMechanical Systems (CMEMS), University of Minho, Campus Azurém, 4800-058 Guimarães, Portugal (S.O.C.); (Ó.C.)
- LABBELS—Associate Laboratory, 4710-057 Braga, Portugal
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16
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Nitzsche A, Hennig CL, von Brandenstein K, Döding A, Schulze-Späte U, Symmank J, Jacobs C. GDF15 Modulates the Zoledronic-Acid-Induced Hyperinflammatory Mechanoresponse of Periodontal Ligament Fibroblasts. Cells 2024; 13:147. [PMID: 38247838 PMCID: PMC10814077 DOI: 10.3390/cells13020147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/29/2023] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
Orthodontic tooth movement (OTM) is thought to be impeded by bisphosphonate (BP) therapy, mainly due to increased osteoclast apoptosis and changes in the periodontal ligament (PdL), a connecting tissue between the alveolar bone and teeth. PdL cells, mainly fibroblasts (PdLFs), are crucial regulators in OTM by modulating force-induced local inflammatory processes. Recently, we identified the TGF-β/BMP superfamily member GDF15 as an important modulator in OTM, promoting the pro-inflammatory mechanoresponses of PdLFs. The precise impact of the highly potent BP zoledronate (ZOL) on the mechanofunctionality of PdLFs is still under-investigated. Therefore, the aim of this study was to further characterize the ZOL-induced changes in the initial inflammatory mechanoresponse of human PdLFs (hPdLFs) and to further clarify a potential interrelationship with GDF15 signaling. Thus, two-day in vitro treatment with 0.5 µM, 5 µM and 50 µM of ZOL altered the cellular properties of hPdLFs partially in a concentration-dependent manner. In particular, exposure to ZOL decreased their metabolic activity, the proliferation rate, detected using Ki-67 immunofluorescent staining, and survival, analyzed using trypan blue. An increasing occurrence of DNA strand breaks was observed using TUNEL and an activated DNA damage response was demonstrated using H2A.X (phosphoS139) staining. While the osteogenic differentiation of hPdLFs was unaffected by ZOL, increased cellular senescence was observed using enhanced p21Waf1/Cip1/Sdi1 and β-galactosidase staining. In addition, cytokine-encoding genes such as IL6, IL8, COX2 and GDF15, which are associated with a senescence-associated secretory phenotype, were up-regulated by ZOL. Subsequently, this change in the hPdLF phenotype promoted a hyperinflammatory response to applied compressive forces with an increased expression of the pro-inflammatory markers IL1β, IL6 and GDF15, as well as the activation of monocytic THP1 cells. GDF15 appeared to be particularly relevant to these changes, as siRNA-mediated down-regulation balanced these hyperinflammatory responses by reducing IL-1β and IL-6 expression (IL1B p-value < 0.0001; IL6 p-value < 0.001) and secretion (IL-1β p-value < 0.05; IL-6 p-value < 0.001), as well as immune cell activation (p-value < 0.0001). In addition, ZOL-related reduced RANKL/OPG values and inhibited osteoclast activation were enhanced in GDF15-deficient hPdLFs (both p-values < 0.0001; all statistical tests: one-way ANOVA, Tukey's post hoc test). Thus, GDF15 may become a promising new target in the personalized orthodontic treatment of bisphosphonatepatients.
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Affiliation(s)
- Ann Nitzsche
- Department of Orthodontics, University Hospital Jena, Leutragraben 3, 07743 Jena, Germany; (A.N.); (C.-L.H.); (K.v.B.); (C.J.)
| | - Christoph-Ludwig Hennig
- Department of Orthodontics, University Hospital Jena, Leutragraben 3, 07743 Jena, Germany; (A.N.); (C.-L.H.); (K.v.B.); (C.J.)
| | - Katrin von Brandenstein
- Department of Orthodontics, University Hospital Jena, Leutragraben 3, 07743 Jena, Germany; (A.N.); (C.-L.H.); (K.v.B.); (C.J.)
| | - Annika Döding
- Section of Geriodontics, Department of Conservative Dentistry and Periodontics, University Hospital Jena, Leutragraben 3, 07743 Jena, Germany; (A.D.); (U.S.-S.)
| | - Ulrike Schulze-Späte
- Section of Geriodontics, Department of Conservative Dentistry and Periodontics, University Hospital Jena, Leutragraben 3, 07743 Jena, Germany; (A.D.); (U.S.-S.)
| | - Judit Symmank
- Department of Orthodontics, University Hospital Jena, Leutragraben 3, 07743 Jena, Germany; (A.N.); (C.-L.H.); (K.v.B.); (C.J.)
| | - Collin Jacobs
- Department of Orthodontics, University Hospital Jena, Leutragraben 3, 07743 Jena, Germany; (A.N.); (C.-L.H.); (K.v.B.); (C.J.)
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17
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Benahmed AG, Tippairote T, Gasmi A, Noor S, Avdeev O, Shanaida Y, Mojgani N, Emadali A, Dadar M, Bjørklund G. Periodontitis Continuum: Antecedents, Triggers, Mediators, and Treatment Strategies. Curr Med Chem 2024; 31:6775-6800. [PMID: 39428847 DOI: 10.2174/0109298673265862231020051338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/28/2023] [Accepted: 09/11/2023] [Indexed: 10/22/2024]
Abstract
Periodontitis (PD) is a chronic inflammatory disease of the periodontium characterized by the formation of gingival pockets and gingival recession. The local inflammatory environment can lead to the destruction of the extracellular matrix and subsequent bone loss. The pathophysiology of PD involves interactions between genetic predisposition, lifestyle, environmental factors, the oral microbiota condition, systemic health disorders, innate and adaptive immune responses, and various host defenses. The review highlighted the importance of the oral cavity condition in systemic health. Thus, a correlation between harmful oral microbiota and cardiovascular disease (CVD)/diabetes/ arthritis, etc, progressions through inflammation and bacterial translocation was highlighted. Antecedents increase an individual's risk of developing PD, trigger initiate microbe-host immunologic responses, and mediators sustain inflammatory interactions. Generally, this review explores the antecedents, triggers, and mediators along the pathophysiological continuum of PD. An analysis of modern approaches to treating periodontitis, including antibiotics for systemic and local use, was carried out. The potential role of natural ingredients such as herbal extracts, phytoconstituents, propolis, and probiotics in preventing and treating PD was highlighted.
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Affiliation(s)
| | - Torsak Tippairote
- Department of Research, HP Medical Centre, Bangkok, Thailand
- Thailand Initiatives for Functional Medicine, Bangkok, Thailand
| | - Amin Gasmi
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Sadaf Noor
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| | - Oleksandr Avdeev
- Pediatric Dentistry Department, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Yurii Shanaida
- Pediatric Dentistry Department, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Naheed Mojgani
- Biotechnology Department, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization, Karaj, Iran
| | - Alireza Emadali
- School of Dentistry Medicine, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Dadar
- Department of Research, CONEM Iran Microbiology Research Group, Tehran, Iran
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway
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18
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Shen X, Wu W, Ying Y, Zhou L, Zhu H. A regulatory role of Piezo1 in apoptosis of periodontal tissue and periodontal ligament fibroblasts during orthodontic tooth movement. AUST ENDOD J 2023; 49 Suppl 1:228-237. [PMID: 36461169 DOI: 10.1111/aej.12721] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/25/2022] [Accepted: 11/16/2022] [Indexed: 12/04/2022]
Abstract
Investigation on the effect of Piezo1 on periodontal tissue and periodontal ligament fibroblasts (PDLFs) under mechanical stress and the underlying mechanism. The orthodontic tooth movement rat model was established via an orthodontic spiral tension spring. PDLFs were cultured and subjected to 2.0 g/cm2 static compressive loading. Blocked the Piezo1 via Piezo1 inhibitor, GsMTx4. TUNEL staining and flow cytometry determined the apoptosis rate of periodontal tissue and PDLFs in rats. Expression of Piezo1, p-p38 and ERK1/2 was analysed by immunofluorescence assay and western blotting. Piezo1 inhibitor GsMTx4 relieved the increased expression of Piezo1, ERK1/2 and p-p38, and alleviated apoptosis in periodontal tissue and PDLFs under compressive loading. Piezo1 inhibition can alleviate force-induced apoptosis and damage in rats' periodontal tissue and PDLFs, and regulate the p38/ERK1/2 signalling pathway.
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Affiliation(s)
- Xuanjiang Shen
- Department of Stomatology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weilli Wu
- Department of Stomatology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yukang Ying
- Department of Stomatology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Liyuan Zhou
- Department of Stomatology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Haiqian Zhu
- Department of Stomatology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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19
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Rajeshwari HRS, Kishen A. Periodontal Fibroblasts-Macrophage Crosstalk in External Inflammatory Root Resorption. J Endod 2023; 49:1145-1153.e3. [PMID: 37268291 DOI: 10.1016/j.joen.2023.05.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/04/2023]
Abstract
INTRODUCTION This study aimed to understand the influence of periodontal fibroblasts (PDLFs) on clastic differentiation of macrophages (Mφ) in different resorptive environments. METHODS PDLF-Mφ direct coculture (juxtacrine) was seeded on dentin, cementum, and polystyrene with/without lipopolysaccharide, macrophage colony-stimulating factor, and receptor activator of nuclear factor kappa beta ligand for 7 and 14 days and stained for tartrate-resistant acid phosphatase (TRAP) activity. PDLF-Mφ cocultured on polystyrene were immunostained for CD80, CD206, NFATc1, STAT6, and periostin, and cell culture supernatants were assessed for cytokines on days 2 and 7. Mφ grown in conditioned media of PDLFs (paracrine) and Mφ monoculture were used as controls. Data was analyzed using Student t test and one-way analysis of variance with the Tukey multiple comparisons test (P < .05). RESULTS PDLF-Mφ coculture showed a higher number of TRAP-positive multinucleated cells than Mφ monoculture on dentin and polystyrene. No TRAP-positive multinucleated cells were observed in paracrine and cementum. The expression of CD80 and CD206 in PDLF-Mφ was similar at day 2, whereas CD206 was greater than CD80 at day 7. The expression of STAT6 was greater than NFATc1 at both days 2 and 7 (P < .05). Periostin expression in the presence of the lipopolysaccharide, macrophage colony-stimulating factor, and receptor activator of nuclear factor kappa beta ligand combination was down-regulated in PDLF monoculture, whereas it was up-regulated in PDLF-Mφ coculture. The cytokine profile of PDLF-Mφ on day 2 was predominated by interleukin (IL)-1β, tumor necrosis factor alpha, and MMP9 and MMP2 on day 7. IL-6 and IL-8 showed steady expression at both days 2 and 7. CONCLUSIONS The study highlights the juxtacrine effect of PDLFs on the clastic differentiation of Mφ with a difference in clastic activity between dentin and cementum. The study also emphasizes the temporal effect of tumor necrosis factor alpha, MMP2, MMP9, and IL-1β on intercellular crosstalk in resorptive environments.
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Affiliation(s)
| | - Anil Kishen
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, Ontario, Canada; Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; School of Graduate Studies, University of Toronto, Toronto, Ontario, Canada; Department of Dentistry, Mount Sinai Health System, Mount Sinai Hospital, Toronto, Ontario, Canada.
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20
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Wang X, Liu Q, Peng J, Song W, Zhao J, Chen L. The Effects and Mechanisms of PBM Therapy in Accelerating Orthodontic Tooth Movement. Biomolecules 2023; 13:1140. [PMID: 37509176 PMCID: PMC10377711 DOI: 10.3390/biom13071140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/11/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Malocclusion is one of the three major diseases, the incidence of which could reach 56% of the imperiled oral and systemic health in the world today. Orthodontics is still the primary method to solve the problem. However, it is clear that many orthodontic complications are associated with courses of long-term therapy. Photobiomodulation (PBM) therapy could be used as a popular way to shorten the course of orthodontic treatment by nearly 26% to 40%. In this review, the efficacy in cells and animals, mechanisms, relevant cytokines and signaling, clinical trials and applications, and the future developments of PBM therapy in orthodontics were evaluated to demonstrate its validity. Simultaneously, based on orthodontic mechanisms and present findings, the mechanisms of acceleration of orthodontic tooth movement (OTM) caused by PBM therapy were explored in relation to four aspects, including blood vessels, inflammatory response, collagen and fibers, and mineralized tissues. Also, the cooperative effects and clinical translation of PBM therapy in orthodontics have been explored in a growing numbers of studies. Up to now, PBM therapy has been gaining popularity for its non-invasive nature, easy operation, and painless procedures. However, the validity and exact mechanism of PBM therapy as an adjuvant treatment in orthodontics have not been fully elucidated. Therefore, this review summarizes the efficacy of PBM therapy on the acceleration of OTM comprehensively from various aspects and was designed to provide an evidence-based platform for the research and development of light-related orthodontic tooth movement acceleration devices.
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Affiliation(s)
- Xinyuan Wang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Qian Liu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Jinfeng Peng
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Wencheng Song
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Jiajia Zhao
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
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21
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Fragoulis A, Tohidnezhad M, Kubo Y, Wruck CJ, Craveiro RB, Bock A, Wolf M, Pufe T, Jahr H, Suhr F. The Contribution of the Nrf2/ARE System to Mechanotransduction in Musculoskeletal and Periodontal Tissues. Int J Mol Sci 2023; 24:ijms24097722. [PMID: 37175428 PMCID: PMC10177782 DOI: 10.3390/ijms24097722] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/17/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Mechanosensing plays an essential role in maintaining tissue functions. Across the human body, several tissues (i.e., striated muscles, bones, tendons, ligaments, as well as cartilage) require mechanical loading to exert their physiological functions. Contrary, mechanical unloading triggers pathological remodeling of these tissues and, consequently, human body dysfunctions. At the cellular level, both mechanical loading and unloading regulate a wide spectrum of cellular pathways. Among those, pathways regulated by oxidants such as reactive oxygen species (ROS) represent an essential node critically controlling tissue organization and function. Hence, a sensitive balance between the generation and elimination of oxidants keeps them within a physiological range. Here, the Nuclear Factor-E2-related factor 2/Antioxidant response element (Nrf2/ARE) system plays an essential role as it constitutes the major cellular regulation against exogenous and endogenous oxidative stresses. Dysregulations of this system advance, i.a., liver, neurodegenerative, and cancer diseases. Herein, we extend our comprehension of the Nrf2 system to the aforementioned mechanically sensitive tissues to explore its role in their physiology and pathology. We demonstrate the relevance of it for the tissues' functionality and highlight the imperative to further explore the Nrf2 system to understand the physiology and pathology of mechanically sensitive tissues in the context of redox biology.
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Affiliation(s)
- Athanassios Fragoulis
- Department of Anatomy and Cell Anatomy, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Mersedeh Tohidnezhad
- Department of Anatomy and Cell Anatomy, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Yusuke Kubo
- Department of Anatomy and Cell Anatomy, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Christoph Jan Wruck
- Department of Anatomy and Cell Anatomy, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Rogerio Bastos Craveiro
- Department of Orthodontics, Dental Clinic, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Anna Bock
- Department of Oral and Maxillofacial Surgery, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Michael Wolf
- Department of Orthodontics, Dental Clinic, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Thomas Pufe
- Department of Anatomy and Cell Anatomy, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Holger Jahr
- Department of Anatomy and Cell Anatomy, Uniklinik RWTH Aachen, RWTH Aachen University, 52074 Aachen, Germany
- Institute of Structural Mechanics and Lightweight Design, RWTH Aachen University, 52062 Aachen, Germany
| | - Frank Suhr
- Division of Molecular Exercise Physiology, Faculty of Life Sciences: Food, Nutrition and Health, University of Bayreuth, 95326 Kulmbach, Germany
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22
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Pigeaud KE, Rietveld ML, Witvliet AF, Hogervorst JMA, Zhang C, Forouzanfar T, Bravenboer N, Schoenmaker T, de Vries TJ. The Effect of Sclerostin and Monoclonal Sclerostin Antibody Romosozumab on Osteogenesis and Osteoclastogenesis Mediated by Periodontal Ligament Fibroblasts. Int J Mol Sci 2023; 24:ijms24087574. [PMID: 37108735 PMCID: PMC10145870 DOI: 10.3390/ijms24087574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/06/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Sclerostin is a bone formation inhibitor produced by osteocytes. Although sclerostin is mainly expressed in osteocytes, it was also reported in periodontal ligament (PDL) fibroblasts, which are cells that play a role in both osteogenesis and osteoclastogenesis. Here, we assess the role of sclerostin and its clinically used inhibitor, romosozumab, in both processes. For osteogenesis assays, human PDL fibroblasts were cultured under control or mineralizing conditions with increasing concentrations of sclerostin or romosozumab. For analyzing osteogenic capacity and alkaline phosphatase (ALP) activity, alizarin red staining for mineral deposition and qPCR of osteogenic markers were performed. Osteoclast formation was investigated in the presence of sclerostin or romosozumab and, in PDLs, in the presence of fibroblasts co-cultured with peripheral blood mononuclear cells (PBMCs). PDL-PBMC co-cultures stimulated with sclerostin did not affect osteoclast formation. In contrast, the addition of romosozumab slightly reduced the osteoclast formation in PDL-PBMC co-cultures at high concentrations. Neither sclerostin nor romosozumab affected the osteogenic capacity of PDL fibroblasts. qPCR analysis showed that the mineralization medium upregulated the relative expression of osteogenic markers, but this expression was barely affected when romosozumab was added to the cultures. In order to account for the limited effects of sclerostin or romosozumab, we finally compared the expression of SOST and its receptors LRP-4, -5, and -6 to the expression in osteocyte rich-bone. The expression of SOST, LRP-4, and LRP-5 was higher in osteocytes compared to in PDL cells. The limited interaction of sclerostin or romosozumab with PDL fibroblasts may relate to the primary biological function of the periodontal ligament: to primarily resist bone formation and bone degradation to the benefit of an intact ligament that is indented by every chew movement.
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Affiliation(s)
- Karina E Pigeaud
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Melanie L Rietveld
- Amsterdam University College, University of Amsterdam and Vrije Universiteit, Science Park 113, 1098 XG Amsterdam, The Netherlands
| | - Aster F Witvliet
- Amsterdam University College, University of Amsterdam and Vrije Universiteit, Science Park 113, 1098 XG Amsterdam, The Netherlands
| | - Jolanda M A Hogervorst
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 LA Amsterdam, The Netherlands
| | - Chen Zhang
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 LA Amsterdam, The Netherlands
- Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Tim Forouzanfar
- Oral Pathology and 3D Innovation Lab, Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 LA Amsterdam, The Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Teun J de Vries
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
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Huang X, Li Y, Liao H, Luo X, Zhao Y, Huang Y, Zhou Z, Xiang Q. Research Advances on Stem Cell-Derived Extracellular Vesicles Promoting the Reconstruction of Alveolar Bone through RANKL/RANK/OPG Pathway. J Funct Biomater 2023; 14:jfb14040193. [PMID: 37103283 PMCID: PMC10145790 DOI: 10.3390/jfb14040193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/17/2023] [Accepted: 03/27/2023] [Indexed: 04/28/2023] Open
Abstract
Periodontal bone tissue defects and bone shortages are the most familiar and troublesome clinical problems in the oral cavity. Stem cell-derived extracellular vesicles (SC-EVs) have biological properties similar to their sources, and they could be a promising acellular therapy to assist with periodontal osteogenesis. In the course of alveolar bone remodeling, the RANKL/RANK/OPG signaling pathway is an important pathway involved in bone metabolism. This article summarizes the experimental studies of SC-EVs applied for the therapy of periodontal osteogenesis recently and explores the role of the RANKL/RANK/OPG pathway in their mechanism of action. Their unique patterns will open a new field of vision for people, and they will help to advance a possible future clinical treatment.
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Affiliation(s)
- Xia Huang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
- School of Stomatology, Jinan University, Guangzhou 510632, China
- Department of Orthodontics, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Yuxiao Li
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
- School of Stomatology, Jinan University, Guangzhou 510632, China
| | - Hui Liao
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Xin Luo
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Yueping Zhao
- School of Stomatology, Jinan University, Guangzhou 510632, China
| | - Yadong Huang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Zhiying Zhou
- School of Stomatology, Jinan University, Guangzhou 510632, China
- Department of Orthodontics, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Qi Xiang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
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24
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Recent Clinical Treatment and Basic Research on the Alveolar Bone. Biomedicines 2023; 11:biomedicines11030843. [PMID: 36979821 PMCID: PMC10044990 DOI: 10.3390/biomedicines11030843] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/07/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
The periodontal ligament is located between the bone (alveolar bone) and the cementum of the tooth, and it is connected by tough fibers called Sharpey’s fibers. To maintain healthy teeth, the foundation supporting the teeth must be healthy. Periodontal diseases, also known as tooth loss, cause the alveolar bone to dissolve. The alveolar bone, similar to the bones in other body parts, is repeatedly resorbed by osteoclasts and renewed by osteogenic cells. This means that an old bone is constantly being resorbed and replaced by a new bone. In periodontal diseases, the alveolar bone around the teeth is absorbed, and as the disease progresses, the alveolar bone shrinks gradually. In most cases, the resorbed alveolar bone does not return to its original form even after periodontal disease is cured. Gum covers the tooth surface so that it matches the shape of the resorbed alveolar bone, exposing more of the tooth surface than before, making the teeth look longer, leaving gaps between the teeth, and in some cases causing teeth to sting. Previously, the only treatment for periodontal diseases was to stop the disease from progressing further before the teeth fell out, and restoration to the original condition was almost impossible. However, a treatment method that can help in the regeneration of the supporting tissues of the teeth destroyed by periodontal diseases and the restoration of the teeth to their original healthy state as much as possible is introduced. Recently, with improvements in implant material properties, implant therapy has become an indispensable treatment method in dentistry and an important prosthetic option. Treatment methods and techniques, which are mainly based on experience, have gradually accumulated scientific evidence, and the number of indications for treatment has increased. The development of bone augmentation methods has contributed remarkably to the expansion of indications, and this has been made possible by various advances in materials science. The induced pluripotent stem cell (iPS) cell technology for regenerating periodontal tissues, including alveolar bone, is expected to be applied in the treatment of diseases, such as tooth loss and periodontitis. This review focuses on the alveolar bone and describes clinical practice, techniques, and the latest basic research.
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25
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Wang W, Song Y, Tian Y, Chen B, Liang Y, Liang Y, Li C, Li Y. TCPP/MgO-loaded PLGA microspheres combining photodynamic antibacterial therapy with PBM-assisted fibroblast activation to treat periodontitis. Biomater Sci 2023; 11:2828-2844. [PMID: 36857622 DOI: 10.1039/d2bm01959k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Bacteria eradication and subsequent periodontal tissue reconstruction is the primary task for periodontitis treatment. Commonly used antibiotic therapy suffers from antibiotic resistance. Meanwhile, promoting fibroblast activity is crucial for re-establishing a damaged periodontal structure. In addition to the fibroblast activation property of Mg2+, photobiomodulation (PBM) has recently attracted increasing attention in wound healing. Using the same 635 nm laser resource, PBM could simultaneously work with antibacterial photodynamic therapy (aPDT) to achieve antibacterial function and fibroblast activation effect. Herein, multifunctional microspheres were designed by employing poly (lactic-co-glycolic acid) (PLGA) microspheres to load tetrakis (4-carboxyphenyl) porphyrin (TCPP) and magnesium oxide (MgO) nanoparticles, named as PMT, with sustained Mg2+ release for 20 days. PMT achieved excellent antibacterial photodynamic effect for periodontal pathogens F. nucleatum and P. gingivalis by generating reactive oxygen species, which increases cell membrane permeability and destroys bacteria integrity to cause bacteria death. Meanwhile, PMT itself exhibited improved fibroblast viability and adhesion, with the PMT + light group revealing further activation of fibroblast cells, suggesting the coordinated action of Mg2+ and PBM effects. The underlying molecular mechanism might be the elevated gene expressions of Fibronectin 1, Col1a1, and Vinculin. In addition, the in vivo rat periodontitis model proved the superior therapeutic effects of PMT with laser illumination using micro-computed tomography analysis and histological staining, which presented decreased inflammatory cells, increased collagen production, and higher alveolar bone level in the PMT group. Our study sheds light on a promising strategy to fight periodontitis using versatile microspheres, which combine aPDT and PBM-assisted fibroblast activation functions.
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Affiliation(s)
- Wanmeng Wang
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
| | - Yunjia Song
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
| | - Yuan Tian
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
| | - Bo Chen
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
| | - Yunkai Liang
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
| | - Yu Liang
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
| | - Changyi Li
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
| | - Ying Li
- School of Dentistry, Tianjin Medical University, Tianjin 300070, China.
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26
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Chen Y, Zhang C. Role of noncoding RNAs in orthodontic tooth movement: new insights into periodontium remodeling. J Transl Med 2023; 21:101. [PMID: 36759852 PMCID: PMC9912641 DOI: 10.1186/s12967-023-03951-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 02/01/2023] [Indexed: 02/11/2023] Open
Abstract
Orthodontic tooth movement (OTM) is biologically based on the spatiotemporal remodeling process in periodontium, the mechanisms of which remain obscure. Noncoding RNAs (ncRNAs), especially microRNAs and long noncoding RNAs, play a pivotal role in maintaining periodontal homeostasis at the transcriptional, post-transcriptional, and epigenetic levels. Under force stimuli, mechanosensitive ncRNAs with altered expression levels transduce mechanical load to modulate intracellular genes. These ncRNAs regulate the biomechanical responses of periodontium in the catabolic, anabolic, and coupling phases throughout OTM. To achieve this, down or upregulated ncRNAs actively participate in cell proliferation, differentiation, autophagy, inflammatory, immune, and neurovascular responses. This review highlights the regulatory mechanism of fine-tuning ncRNAs in periodontium remodeling during OTM, laying the foundation for safe, precise, and personalized orthodontic treatment.
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Affiliation(s)
- Yuming Chen
- grid.284723.80000 0000 8877 7471Stomatological Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Chao Zhang
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China.
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27
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Kim J, Kim JY, Bhattarai G, So HS, Kook SH, Lee JC. Periodontal Ligament-Mimetic Fibrous Scaffolds Regulate YAP-Associated Fibroblast Behaviors and Promote Regeneration of Periodontal Defect in Relation to the Scaffold Topography. ACS APPLIED MATERIALS & INTERFACES 2023; 15:599-616. [PMID: 36575925 PMCID: PMC9837821 DOI: 10.1021/acsami.2c18893] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023]
Abstract
Although multiple regenerative strategies are being developed for periodontal reconstruction, guided periodontal ligament (PDL) regeneration is difficult because of its cellular and fibrous complexities. Here, we manufactured four different types of PDL-mimic fibrous scaffolds on a desired single mat. These scaffolds exhibited a structure of PDL matrix and human PDL fibroblasts (PDLFs) cultured on the scaffolds resembling morphological phenotypes present in native PDLF. The scaffold-seeded PDLF exerted proliferative, osteoblastic, and osteoclastogenic potentials depending on the fiber topographical cues. Fiber surface-regulated behaviors of PDLF were correlated with the expression patterns of yes-associated protein (YAP), CD105, periostin, osteopontin, and vinculin. Transfection with si-RNA confirmed that YAP acted as the master mechanosensing regulator. Of the as-spun scaffolds, aligned or grid-patterned microscale scaffold regulated the YAP-associated behavior of PDLF more effectively than nanomicroscale or random-oriented microscale scaffold. Implantation with hydrogel complex conjugated with microscale-patterned or grid-patterned scaffold, but not other types of scaffolds, recovered the defected PDL with native PDL-mimic cellularization and fiber structure in the reformed PDL. Our results demonstrate that PDL-biomimetic scaffolds regulate topography-related and YAP-mediated behaviors of PDLF in relation to their topographies. Overall, this study may support a clinical approach of the fiber-hydrogel complex in guided PDL regenerative engineering.
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Affiliation(s)
- Jeong
In Kim
- Cluster
for Craniofacial Development and Regeneration Research, Institute
of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea
| | - Ju Yeon Kim
- Department
of Bionanosystem Engineering, Jeonbuk National
University, Jeonju 54896, South Korea
| | - Govinda Bhattarai
- Cluster
for Craniofacial Development and Regeneration Research, Institute
of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea
| | - Han-Sol So
- Department
of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea
| | - Sung-Ho Kook
- Department
of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea
| | - Jeong-Chae Lee
- Cluster
for Craniofacial Development and Regeneration Research, Institute
of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea
- Department
of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea
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[68Ga]Ga-Pentixafor and Sodium [18F]Fluoride PET Can Non-Invasively Identify and Monitor the Dynamics of Orthodontic Tooth Movement in Mouse Model. Cells 2022; 11:cells11192949. [PMID: 36230911 PMCID: PMC9562206 DOI: 10.3390/cells11192949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/15/2022] [Accepted: 09/17/2022] [Indexed: 12/02/2022] Open
Abstract
The cellular and molecular mechanisms of orthodontic tooth movement (OTM) are not yet fully understood, partly due to the lack of dynamical datasets within the same subject. Inflammation and calcification are two main processes during OTM. Given the high sensitivity and specificity of [68Ga]Ga-Pentixafor and Sodium [18F]Fluoride (Na[18F]F) for inflammation and calcification, respectively, the aim of this study is to assess their ability to identify and monitor the dynamics of OTM in an established mouse model. To monitor the processes during OTM in real time, animals were scanned using a small animal PET/CT during week 1, 3, and 5 post-implantation, with [68Ga]Ga-Pentixafor and Na[18F]F. Both tracers showed an increased uptake in the region of interest compared to the control. For [68Ga]Ga-Pentixafor, an increased uptake was observed within the 5-week trial, suggesting the continuous presence of inflammatory markers. Na[18F]F showed an increased uptake during the trial, indicating an intensification of bone remodelling. Interim and end-of-experiment histological assessments visualised increased amounts of chemokine receptor CXCR4 and TRAP-positive cells in the periodontal ligament on the compression side. This approach establishes the first in vivo model for periodontal remodelling during OTM, which efficiently detects and monitors the intricate dynamics of periodontal ligament.
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Guo K, Zhao H, Chen G, Zhang Y, Wang Y, Huo L, Sun S, Wei W. PAP Polypeptide Promotes Osteogenesis in Jaw Bone Defect Repair by Inhibiting Inflammatory Reactions. Front Bioeng Biotechnol 2022; 10:916330. [PMID: 35721849 PMCID: PMC9201685 DOI: 10.3389/fbioe.2022.916330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/12/2022] [Indexed: 11/13/2022] Open
Abstract
Jaw defects are common in oral and maxillofacial diseases and require surgical repair in extreme cases. Given the limitations in availability and efficacy of autologous bone grafts or allografts, great effort has been made in finding suitable, biocompatible, and effective artificial bone materials. Considering the key role of inflammation in bone resorption, we sought to identify a polypeptide with anti-inflammatory and bone-promoting effects. Rat bone marrow-derived mesenchymal cells (BMSCs) were treated with lipopolysaccharide (LPS) to induce an inflammatory environment, and 1,538 differentially abundant polypeptides were identified using mass spectrometry. Based on mass spectrometry signal intensity, multiple of difference, and structural stability, PAP was screened out as the polypeptide with the lowest abundance in the inflammatory condition. PAP showed no cytotoxicity to BMSCs with increasing concentrations. PAP (10 μM) also increased alkaline phosphatase activity and mRNA expression of Ocn, Bmp2, and Runx2 in a concentration-dependent manner, which confirmed that it can promote osteogenic induction of rat BMSCs. Moreover, PAP reduced LPS-induced expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and reactive oxygen species and inhibited polarization of RAW 264.7 macrophages to the inflammatory type. Finally, a skull defect mouse model was established, and mice were injected with LPS and/or PAP. Micro-CT, histological analysis, and immunohistochemical staining showed that PAP significantly reduced the number of LPS-induced bone resorption pits and maintained bone integrity. Overall, the polypeptide PAP screened using LPS stimulation of BMSCs is not cytotoxic and can inhibit the inflammatory reaction process to promote osteogenesis. This study thus provides a basis for development of PAP as a new osteogenic material in the repair of jaw defects.
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Affiliation(s)
- Ke Guo
- Department of Stomatology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haoming Zhao
- Department of Stomatology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guokun Chen
- Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Zhang
- Department of Stomatology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Wang
- Nursing Department, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Huo
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Liang Huo, ; Shoufu Sun, ; Wenjia Wei,
| | - Shoufu Sun
- Department of Stomatology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Liang Huo, ; Shoufu Sun, ; Wenjia Wei,
| | - Wenjia Wei
- Department of Stomatology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Liang Huo, ; Shoufu Sun, ; Wenjia Wei,
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30
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Kuo CH, Zhang BH, Huang SE, Hsu JH, Wang YH, Nguyen TTN, Lai CH, Yeh JL. Xanthine Derivative KMUP-1 Attenuates Experimental Periodontitis by Reducing Osteoclast Differentiation and Inflammation. Front Pharmacol 2022; 13:821492. [PMID: 35571109 PMCID: PMC9097136 DOI: 10.3389/fphar.2022.821492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/21/2022] [Indexed: 11/24/2022] Open
Abstract
Periodontitis is an inflammatory disease of gum that may predispose to serious systemic complications such as diabetes and cardiovascular diseases. Activation of macrophages and osteoclasts around periodontal tissue can accelerate gum inflammation. In addition, alteration of cyclic nucleotide levels is associated with the severity of periodontitis. Our previous study has shown that KMUP-1, a xanthine derivative exhibiting phosphodiesterase inhibition and soluble guanylyl cyclase activation, can inhibit lipopolysaccharide (LPS)-induced inflammation and receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. This study was aimed to investigate whether KMUP-1 could attenuate periodontitis both in vitro and in vivo. In vitro, the protective effect of KMUP-1 on inflammation and osteoclastogenesis was investigated in RANKL-primed RAW264.7 cells treated by Porphyromonas gingivalis LPS (PgLPS). The results showed that KMUP-1 attenuated PgLPS-induced osteoclast differentiation as demonstrated by decreased TRAP-positive multinuclear cells and TRAP activity. This reduction of osteoclast differentiation by KMUP-1 was reversed by KT5823, a protein kinase G inhibitor. Similarly, pro-inflammatory cytokine levels induced by PgLPS were inhibited by KMUP-1 in a dose-dependent manner whereas reversed by KT5823. Mechanistically, suppression of MAPKs, PI3K/Akt, and NF-κB signaling pathways and decrease of c-Fos and NFATc1 expression in osteoclast precursors by KMUP-1 may mediate its protective effect. In vivo, two models of periodontitis in rats were induced by gingival injections of PgLPS and ligature placement around molar teeth, respectively. Our results showed that KMUP-1 inhibited alveolar bone loss in both rat models, and this effect mediated at least partly by reduced osteoclastogenesis. In conclusion, our study demonstrated the therapeutic potential of KMUP-1 on periodontitis through suppression of inflammation and osteoclast differentiation.
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Affiliation(s)
- Cheng-Hsiang Kuo
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - Ban-Hua Zhang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shang-En Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jong-Hau Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Pediatrics, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yan-Hsiung Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Thi Tuyet Ngan Nguyen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Han Lai
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jwu-Lai Yeh
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- *Correspondence: Jwu-Lai Yeh,
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Tao LY, Łagosz-Ćwik KB, Hogervorst JMA, Schoenmaker T, Grabiec AM, Forouzanfar T, van der Weijden FA, de Vries TJ. Diabetes Medication Metformin Inhibits Osteoclast Formation and Activity in In Vitro Models for Periodontitis. Front Cell Dev Biol 2022; 9:777450. [PMID: 35096812 PMCID: PMC8793072 DOI: 10.3389/fcell.2021.777450] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Diabetes and periodontitis are comorbidities and may share common pathways. Several reports indicate that diabetes medication metformin may be beneficial for the periodontal status of periodontitis patients. Further research using appropriate cell systems of the periodontium, the tissue that surrounds teeth may reveal the possible mechanism. Periodontal ligament fibroblasts anchor teeth in bone and play a role in the onset of both alveolar bone formation and degradation, the latter by inducing osteoclast formation from adherent precursor cells. Therefore, a cell model including this type of cells is ideal to study the influence of metformin on both processes. We hypothesize that metformin will enhance bone formation, as described for osteoblasts, whereas the effects of metformin on osteoclast formation is yet undetermined. Periodontal ligament fibroblasts were cultured in the presence of osteogenic medium and 0.2 or 1 mM metformin. The influence of metformin on osteoclast formation was first studied in PDLF cultures supplemented with peripheral blood leukocytes, containing osteoclast precursors. Finally, the effect of metformin on osteoclast precursors was studied in cultures of CD14+ monocytes that were stimulated with M-CSF and receptor activator of Nf-κB ligand (RANKL). No effects of metformin were observed on osteogenesis: not on alkaline phosphatase activity, Alizarin red deposition, nor on the expression of osteogenic markers RUNX-2, Collagen I and Osteonectin. Metformin inhibited osteoclast formation and accordingly downregulated the genes involved in osteoclastogenesis: RANKL, macrophage colony stimulating factor (M-CSF) and osteoclast fusion gene DC-STAMP. Osteoclast formation on both plastic and bone as well as bone resorption was inhibited by metformin in M-CSF and RANKL stimulated monocyte cultures, probably by reduction of RANK expression. The present study unraveling the positive effect of metformin in periodontitis patients at the cellular level, indicates that metformin inhibits osteoclast formation and activity, both when orchestrated by periodontal ligament fibroblasts and in cytokine driven osteoclast formation assays. The results indicate that metformin could have a systemic beneficiary effect on bone by inhibiting osteoclast formation and activity.
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Affiliation(s)
- Lucy Y Tao
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Amsterdam, Netherlands.,Amsterdam University College, University of Amsterdam and Vrije University Amsterdam, Amsterdam, Netherlands
| | - Katarzyna B Łagosz-Ćwik
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Jolanda M A Hogervorst
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Amsterdam, Netherlands
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Amsterdam, Netherlands
| | - Aleksander M Grabiec
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Tim Forouzanfar
- Department of Oral and Maxillofacial Surgery and Oral Pathology, Amsterdam UMC, Amsterdam, Netherlands
| | - Fridus A van der Weijden
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Amsterdam, Netherlands
| | - Teun J de Vries
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije University Amsterdam, Amsterdam, Netherlands
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Sedghi LM, Bacino M, Kapila YL. Periodontal Disease: The Good, The Bad, and The Unknown. Front Cell Infect Microbiol 2021; 11:766944. [PMID: 34950607 PMCID: PMC8688827 DOI: 10.3389/fcimb.2021.766944] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/11/2021] [Indexed: 01/08/2023] Open
Abstract
Periodontal disease is classically characterized by progressive destruction of the soft and hard tissues of the periodontal complex, mediated by an interplay between dysbiotic microbial communities and aberrant immune responses within gingival and periodontal tissues. Putative periodontal pathogens are enriched as the resident oral microbiota becomes dysbiotic and inflammatory responses evoke tissue destruction, thus inducing an unremitting positive feedback loop of proteolysis, inflammation, and enrichment for periodontal pathogens. Keystone microbial pathogens and sustained gingival inflammation are critical to periodontal disease progression. However, recent studies have revealed the importance of previously unidentified microbes involved in disease progression, including various viruses, phages and bacterial species. Moreover, newly identified immunological and genetic mechanisms, as well as environmental host factors, including diet and lifestyle, have been discerned in recent years as further contributory factors in periodontitis. These factors have collectively expanded the established narrative of periodontal disease progression. In line with this, new ideologies related to maintaining periodontal health and treating existing disease have been explored, such as the application of oral probiotics, to limit and attenuate disease progression. The role of systemic host pathologies, such as autoimmune disorders and diabetes, in periodontal disease pathogenesis has been well noted. Recent studies have additionally identified the reciprocated importance of periodontal disease in potentiating systemic disease states at distal sites, such as in Alzheimer's disease, inflammatory bowel diseases, and oral cancer, further highlighting the importance of the oral cavity in systemic health. Here we review long-standing knowledge of periodontal disease progression while integrating novel research concepts that have broadened our understanding of periodontal health and disease. Further, we delve into innovative hypotheses that may evolve to address significant gaps in the foundational knowledge of periodontal disease.
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Affiliation(s)
- Lea M. Sedghi
- School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
| | - Margot Bacino
- School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
| | - Yvonne Lorraine Kapila
- School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
- Department of Periodontology, School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
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Hirashima S, Ohta K, Togo A, Nakamura KI. 3D Mesoscopic Architecture of a Heterogeneous Cellular Network in the Cementum-Periodontal Ligament-Alveolar Bone Complex. Microscopy (Oxf) 2021; 71:22-33. [PMID: 34850074 DOI: 10.1093/jmicro/dfab051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/24/2021] [Accepted: 11/26/2021] [Indexed: 11/14/2022] Open
Abstract
Cell-to-cell communication orchestrates various cell and tissue functions. This communication enables cells to form cellular networks with each other through direct contact via intercellular junctions. Because these cellular networks are closely related to tissue and organ functions, elucidating the morphological characteristics of cellular networks could lead to the development of novel therapeutic approaches. The tooth, periodontal ligament (PDL), and alveolar bone form a complex via collagen fibres. Teeth depend on the co-ordinated activity of this complex to maintain their function, with cellular networks in each of its three components. Imaging methods for three-dimensional (3D) mesoscopic architectural analysis include focused ion beam/scanning electron microscopy (FIB/SEM), which is characterised by its ability to select observation points and acquire data from complex tissue after extensive block-face imaging, without the need to prepare numerous ultrathin sections. Previously, we employed FIB/SEM to analyse the 3D mesoscopic architecture of hard tissue including the PDL, which exists between the bone and tooth root. The imaging results showed that the cementum, PDL, and alveolar bone networks are in contact and form a heterogeneous cellular network. This cellular network may orchestrate mechanical loading-induced remodelling of the cementum-PDL-alveolar bone complex as the remodelling of each complex component is coordinated, as exemplified by tooth movement due to orthodontic treatment and tooth dislocation due to occlusal loss. In this review, we summarise and discuss the 3D mesoscopic architecture of cellular networks in the cementum, PDL, and alveolar bone as observed in our recent mesoscopic and morphological studies.
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Affiliation(s)
- Shingo Hirashima
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, 830-0011, Japan.,Dental and Oral Medical Center, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Keisuke Ohta
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, 830-0011, Japan.,Advanced Imaging Research Center, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Akinobu Togo
- Advanced Imaging Research Center, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Kei-Ichiro Nakamura
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, 830-0011, Japan.,Cognitive and Molecular Research Institute of Brain Diseases, Kurume University School of Medicine, Kurume, 830-0011, Japan
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Shen Y, Wang Y, Fu Z, Ma Q, Song Y, Fang L, Chen L. UPR attenuates the proinflammatory effect of HPDLF on macrophage polarization. Cell Stress Chaperones 2021; 26:937-944. [PMID: 34495492 PMCID: PMC8578276 DOI: 10.1007/s12192-021-01234-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 12/24/2022] Open
Abstract
Human periodontal ligament fibroblast (HPDLF) is a major component of the resident cells in the periodontal microenvironment, and plays important roles in periodontitis through multiple mechanisms. Although lipopolysaccharide (LPS) has been shown to cause endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) in HPDLF, the mechanisms governing HPDLF function in periodontitis are unclear. In this study, we tested the ability of unfolded protein response (UPR) to regulate HPDLF in vitro and examined the underlying mechanisms. We found LPS-pretreated HPDLF induced macrophage polarization toward M1 phenotype. UPR activation reduced the inflammatory cytokine production and downregulated the expression of TLR4 in HPDLF. The phosphorylation of NF-κB p65 and I-κB was also inhibited by UPR activation. Our findings demonstrate that the connection of LPS, UPR, and HPDLF may represent a new concrete theory of innate immunity regulation in periodontal diseases, and suggest that targeting of UPR in HPDLF may be developed as a potent therapy for periodontitis.
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Affiliation(s)
- Yuting Shen
- Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, China
| | - Ying Wang
- Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, China
| | - Zhaoyue Fu
- Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, China
| | - Qianli Ma
- Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, China
| | - Yun Song
- Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, China
| | - Liang Fang
- Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, China.
| | - Lihua Chen
- Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, China.
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Apolipoprotein E is an effective biomarker for orthodontic tooth movement in patients treated with transmission straight wire appliances. Am J Orthod Dentofacial Orthop 2021; 161:255-262.e1. [PMID: 34756485 DOI: 10.1016/j.ajodo.2020.08.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 08/01/2020] [Accepted: 08/01/2020] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Orthodontic tooth movement (OTM) is the core component of orthodontic treatment and is increasingly popular for treating malocclusions. In this study, we aimed to investigate the role of apolipoprotein E (ApoE) in OTM. METHODS Thirty patients treated with transmission straight wire technology were selected and longitudinally tracked at 2 different stages of orthodontic treatment (initial 2 months and 12 months of orthodontic treatment). Total saliva was collected and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Western blotting was used to detect the difference in ApoE expression in the saliva samples of the 2 groups. The expression of ApoE was further verified by immunohistochemical staining in a mouse model of tooth movement. RESULTS The results of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry showed significant differences in the components of the salivary peptides in the 2 groups and peptides with a molecular weight of 2010.7 Da were predicted to be ApoE by database analysis. Western blotting further verified a significant difference in the expression of salivary ApoE in the 2 groups. In addition, an OTM model was successfully constructed in mice. The immunohistochemical staining results showed that ApoE expression significantly increased after force loading in the OTM model. CONCLUSIONS This study indicated that ApoE participated in and played a role during OTM in patients treated with transmission straight wire technology. This relationship might be related to alveolar bone reconstruction and root resorption. The results provide new ideas for research on the mechanism of tooth movement using precision medicine based on saliva detection.
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Loo-Kirana R, Gilijamse M, Hogervorst J, Schoenmaker T, de Vries TJ. Although Anatomically Micrometers Apart: Human Periodontal Ligament Cells Are Slightly More Active in Bone Remodeling Than Alveolar Bone Derived Cells. Front Cell Dev Biol 2021; 9:709408. [PMID: 34616725 PMCID: PMC8488427 DOI: 10.3389/fcell.2021.709408] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/19/2021] [Indexed: 01/09/2023] Open
Abstract
The periodontal ligament (PDL) and the alveolar bone are part of the periodontium, a complex structure that supports the teeth. The alveolar bone is continuously remodeled and is greatly affected by several complex oral events, like tooth extraction, orthodontic movement, and periodontitis. Until now, the role of PDL cells in terms of osteogenesis and osteoclastogenesis has been widely studied, whereas surprisingly little is known about the bone remodeling capacity of alveolar bone. Therefore, the purpose of this study was to compare the biological character of human alveolar bone cells and PDL cells in terms of osteogenesis and osteoclastogenesis in vitro. Paired samples of PDL cells and alveolar bone cells from seven patients with compromised general and oral health were collected and cultured. Bone A (early outgrowth) and bone B (late outgrowth) were included. PDL, bone A, bone B cell cultures all had a fibroblast appearance with similar expression pattern of six mesenchymal markers. These cultures were subjected to osteogenesis and osteoclastogenesis assays. For osteoclastogenesis assays, the cells were co-cultured with peripheral blood mononuclear cells, a source for osteoclast precursor cells. The total duration of the experiments was 21 days. Osteogenesis was slightly favored for PDL compared to bone A and B as shown by stronger Alizarin red staining and higher expression of RUNX2 and Collagen I at day 7 and for ALP at day 21. PDL induced approximately two times more osteoclasts than alveolar bone cells. In line with these findings was the higher expression of cell fusion marker DC-STAMP in PDL-PBMC co-cultures compared to bone B at day 21. In conclusion, alveolar bone contains remodeling activity, but to a different extent compared to PDL cells. We showed that human alveolar bone cells can be used as an in vitro model to study bone remodeling.
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Affiliation(s)
- Rebecca Loo-Kirana
- Department of Periodontology, Academic Centre For Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Marjolijn Gilijamse
- Department of Oral and Maxillofacial Surgery and Oral Pathology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands.,Department of Oral and Maxillofacial Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands
| | - Jolanda Hogervorst
- Department of Oral Cell Biology, Academic Centre For Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre For Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Teun J de Vries
- Department of Periodontology, Academic Centre For Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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Jeon HH, Yang CY, Shin MK, Wang J, Patel JH, Chung CH, Graves DT. Osteoblast lineage cells and periodontal ligament fibroblasts regulate orthodontic tooth movement that is dependent on Nuclear Factor-kappa B (NF-kB) activation. Angle Orthod 2021; 91:664-671. [PMID: 33852725 PMCID: PMC8376154 DOI: 10.2319/031520-182.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 02/01/2021] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVES To investigate the role of NF-κB in osteoblast lineage cells and periodontal ligament (PDL) fibroblasts during orthodontic tooth movement (OTM). MATERIALS AND METHODS Transgenic mice that expressed a dominant negative mutant of the inhibitor of kB kinase (IKK-DN) with lineage specific expression in osteoblastic cells and PDL fibroblasts driven by a response element in the collagen1α1 promoter and matched wild-type (WT) mice were examined. A 10-12 g force was applied by a NiTi coil and maintained for 5 or 12 days. OTM distance, PDL width, and bone volume fraction were measured using micro computed tomography. Osteoclast numbers were counted in tartrate-resistant acid phosphatase-stained sections. Activation of nuclear factor kappa B (NF-kB) was assessed by nuclear localization of p65, and the receptor activator of nuclear factor-κB ligand (RANKL) was measured by immunofluorescence and compared to control specimens with no orthodontic force. RESULTS OTM-induced NF-kB activation (p65 nuclear localization) in WT mice was largely blocked in transgenic (TG) mice. OTM was significantly reduced in the TG mice compared to WT mice along with reduced osteoclastogenesis, narrower PDL width, higher bone volume fraction, and reduced RANKL expression. CONCLUSIONS Osteoblast lineage cells and PDL fibroblasts are key contributors to alveolar bone remodeling in OTM through IKKβ dependent NF-κB activation.
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Yan T, Xie Y, He H, Fan W, Huang F. Role of nitric oxide in orthodontic tooth movement (Review). Int J Mol Med 2021; 48:168. [PMID: 34278439 PMCID: PMC8285047 DOI: 10.3892/ijmm.2021.5001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022] Open
Abstract
Nitric oxide (NO) is an ubiquitous signaling molecule that mediates numerous cellular processes associated with cardiovascular, nervous and immune systems. NO also plays an essential role in bone homeostasis regulation. The present review article summarized the effects of NO on bone metabolism during orthodontic tooth movement in order to provide insight into the regulatory role of NO in orthodontic tooth movement. Orthodontic tooth movement is a process in which the periodontal tissue and alveolar bone are reconstructed due to the effect of orthodontic forces. Accumulating evidence has indicated that NO and its downstream signaling molecule, cyclic guanosine monophosphate (cGMP), mediate the mechanical signals during orthodontic-related bone remodeling, and exert complex effects on osteogenesis and osteoclastogenesis. NO has a regulatory effect on the cellular activities and functional states of osteoclasts, osteocytes and periodontal ligament fibroblasts involved in orthodontic tooth movement. Variations of NO synthase (NOS) expression levels and NO production in periodontal tissues or gingival crevicular fluid (GCF) have been found on the tension and compression sides during tooth movement in both orthodontic animal models and patients. Furthermore, NO precursor and NOS inhibitor administration increased and reduced the tooth movement in animal models, respectively. Further research is required in order to further elucidate the underlying mechanisms and the clinical application prospect of NO in orthodontic tooth movement.
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Affiliation(s)
- Tong Yan
- Department of Pediatric Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Yongjian Xie
- Department of Orthodontic Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Hongwen He
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wenguo Fan
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Fang Huang
- Department of Pediatric Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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39
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Ganther S, Radaic A, Malone E, Kamarajan P, Chang NYN, Tafolla C, Zhan L, Fenno JC, Kapila YL. Treponema denticola dentilisin triggered TLR2/MyD88 activation upregulates a tissue destructive program involving MMPs via Sp1 in human oral cells. PLoS Pathog 2021; 17:e1009311. [PMID: 34255809 PMCID: PMC8301614 DOI: 10.1371/journal.ppat.1009311] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 07/23/2021] [Accepted: 05/26/2021] [Indexed: 12/28/2022] Open
Abstract
Periodontal disease is driven by dysbiosis in the oral microbiome, resulting in over-representation of species that induce the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs) in the periodontium. These chronic tissue-destructive inflammatory responses result in gradual loss of tooth-supporting alveolar bone. The oral spirochete Treponema denticola, is consistently found at significantly elevated levels in periodontal lesions. Host-expressed Toll-Like Receptor 2 (TLR2) senses a variety of bacterial ligands, including acylated lipopolysaccharides and lipoproteins. T. denticola dentilisin, a surface-expressed protease complex comprised of three lipoproteins has been implicated as a virulence factor in periodontal disease, primarily due to its proteolytic activity. While the role of acylated bacterial components in induction of inflammation is well-studied, little attention has been given to the potential role of the acylated nature of dentilisin. The purpose of this study was to test the hypothesis that T. denticola dentilisin activates a TLR2-dependent mechanism, leading to upregulation of tissue-destructive genes in periodontal tissue. RNA-sequencing of periodontal ligament cells challenged with T. denticola bacteria revealed significant upregulation of genes associated with extracellular matrix organization and degradation including potentially tissue-specific inducible MMPs that may play novel roles in modulating host immune responses that have yet to be characterized within the context of oral disease. The Gram-negative oral commensal, Veillonella parvula, failed to upregulate these same MMPs. Dentilisin-induced upregulation of MMPs was mediated via TLR2 and MyD88 activation, since knockdown of expression of either abrogated these effects. Challenge with purified dentilisin upregulated the same MMPs while a dentilisin-deficient T. denticola mutant had no effect. Finally, T. denticola-mediated activation of TLR2/MyD88 lead to the nuclear translocation of the transcription factor Sp1, which was shown to be a critical regulator of all T. denticola-dependent MMP expression. Taken together, these data suggest that T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion.
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Affiliation(s)
- Sean Ganther
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
| | - Allan Radaic
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
| | - Erin Malone
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
| | - Pachiyappan Kamarajan
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
| | - Nai-Yuan Nicholas Chang
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
| | - Christian Tafolla
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
| | - Ling Zhan
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
| | - J. Christopher Fenno
- Department of Biological and Material Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Yvonne L. Kapila
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America
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40
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Xie Y, Tang Q, Yu S, Zheng W, Chen G, Huang X, Chen L. Orthodontic Force-Induced BMAL1 in PDLCs Is a Vital Osteoclastic Activator. J Dent Res 2021; 101:177-186. [PMID: 34157911 DOI: 10.1177/00220345211019949] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Orthodontic tooth movement (OTM) depends on periodontal ligament cells (PDLCs) sensing biomechanical stimuli and subsequently releasing signals to initiate alveolar bone remodeling. However, the mechanisms by which PDLCs sense biomechanical stimuli and affect osteoclastic activities are still unclear. This study demonstrates that the core circadian protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) in PDLCs is highly involved in sensing and delivering biomechanical signals. Orthodontic force upregulates BMAL1 expression in periodontal tissues and cultured PDLCs in manners dependent on ERK (extracellular signal-regulated kinase) and AP1 (activator protein 1). Increased BMAL1 expression can enhance secretion of CCL2 (C-C motif chemokine 2) and RANKL (receptor activator of nuclear factor-κB ligand) in PDLCs, which subsequently promotes the recruitment of monocytes that differentiate into osteoclasts. The mechanistic delineation clarifies that AP1 induced by orthodontic force can directly interact with the BMAL1 promoter and activate gene transcription in PDLCs. Localized administration of the ERK phosphorylation inhibitor U0126 or the BMAL1 inhibitor GSK4112 suppressed ERK/AP1/BMAL1 signaling. These treatments dramatically reduced osteoclastic activity in the compression side of a rat orthodontic model, and the OTM rate was almost nonexistent. In summary, our results suggest that force-induced expression of BMAL1 in PDLCs is closely involved in controlling osteoclastic activities during OTM and plays a vital role in alveolar bone remodeling. It could be a useful therapeutic target for accelerating the OTM rate and controlling pathologic bone-remodeling activities.
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Affiliation(s)
- Y Xie
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Q Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - S Yu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - W Zheng
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - G Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - X Huang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - L Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
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41
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Tsai CL, Hung SL, Lee YY, Ho YC, Yang SF. The role of fibroblasts in the modulation of dental pulp inflammation. J Formos Med Assoc 2021; 121:342-349. [PMID: 34049758 DOI: 10.1016/j.jfma.2021.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND/PURPOSE Dental pulp fibroblasts can protect dental pulp from microbial invasion. However, little is known about the interaction between pulp fibroblasts and the immune cells. In this study, the production of proinflammatory cytokines related to inflammatory cell recruitment was evaluated in tumor necrosis factor (TNF)-α-stimulated human dental pulp fibroblasts (HDPFs). The role of TNF-α-stimulated HDPFs in the cell fusion under inflammatory process was determined with the cell co-culture with peripheral blood mononuclear cells (PBMCs). METHODS HDPFs were stimulated with various concentrations of TNF-α, and the secretion of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1 was analyzed by the enzyme-linked immunosorbent assay. The mRNA expression levels of intercellular adhesion molecule-1 (ICAM-1), macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) were determined by real-time quantitative polymerase chain reaction. TNF-α-treated HDPFs were co-cultured with PBMCs for 21 days, and characteristics of cell differentiation were assessed. RESULTS TNF-α induced IL-6, IL-8 and MCP-1 production in HDPFs. Moreover, mRNA expression levels of ICAM-1, M-CSF and OPG were significantly increased in TNF-α-treated HDPFs. Co-culture of TNF-α-treated HDPFs and PBMCs stimulated formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and the F-actin rings were observed in these multinucleated cells. CONCLUSION Our results indicate that under the stimulation of TNF-α, HDPFs may amplify inflammatory response by cytokines production, which in turn can modulate the differentiation of immune cells.
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Affiliation(s)
- Chia-Lun Tsai
- Division of Endodontics and Periodontology, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shan-Ling Hung
- Department of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Oral Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ya-Yun Lee
- Division of Endodontics and Periodontology, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Ching Ho
- Division of Endodontics and Periodontology, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shue-Fen Yang
- Division of Endodontics and Periodontology, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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Ali M, Yang F, Plachokova AS, Jansen JA, Walboomers XF. Application of specialized pro-resolving mediators in periodontitis and peri-implantitis: a review. Eur J Oral Sci 2021; 129:e12759. [PMID: 33565133 PMCID: PMC7986752 DOI: 10.1111/eos.12759] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 11/18/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Scaling and root planning is a key element in the mechanical therapy used for the eradication of biofilm, which is the major etiological factor for periodontitis and peri‐implantitis. However, periodontitis is also a host mediated disease, therefore, removal of the biofilm without adjunctive therapy may not achieve the desired clinical outcome due to persistent activation of the innate and adaptive immune cells. Most recently, even the resident cells of the periodontium, including periodontal ligament fibroblasts, have been shown to produce several inflammatory factors in response to bacterial challenge. With increased understanding of the pathophysiology of periodontitis, more research is focusing on opposing excessive inflammation with specialized pro‐resolving mediators (SPMs). This review article covers the major limitations of current standards of care for periodontitis and peri‐implantitis, and it highlights recent advances and prospects of SPMs in the context of tissue reconstruction and regeneration. Here, we focus primarily on the role of SPMs in restoring tissue homeostasis after periodontal infection.
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Affiliation(s)
- Muhanad Ali
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fang Yang
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Adelina S Plachokova
- Department of Dentistry, Implantology and Periodontology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - John A Jansen
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
| | - X Frank Walboomers
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
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43
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Tamashunas AC, Katiyar A, Zhang Q, Purkayastha P, Singh PK, Chukkapalli SS, Lele TP. Osteoprotegerin is sensitive to actomyosin tension in human periodontal ligament fibroblasts. J Cell Physiol 2021; 236:5715-5724. [PMID: 33400284 DOI: 10.1002/jcp.30256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/28/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022]
Abstract
Periodontal ligament fibroblasts (PdLFs) are an elongated cell type in the periodontium with matrix and bone regulatory functions which become abnormal in periodontal disease (PD). Here we found that the normally elongated and oriented PdLF nucleus becomes rounded and loses orientation in a mouse model of PD. Using in vitro micropatterning of cultured primary PdLF cell shape, we show that PdLF elongation correlates with nuclear elongation and the presence of thicker, contractile F-actin fibers. The rounded nuclei in mouse PD models in vivo are, therefore, indicative of reduced actomyosin tension. Inhibiting actomyosin contractility by inhibiting myosin light chain kinase, Rho kinase or myosin ATPase activity, in cultured PdLFs each consistently reduced messenger RNA levels of bone regulatory protein osteoprotegerin (OPG). Infection of cultured PdLFs with two different types of periodontal bacteria (Porphyromonas gingivalis and Fusobacterium nucleatum) failed to recapitulate the observed nuclear rounding in vivo, upregulated nonmuscle myosin II phosphorylation and downregulated OPG. Collectively, our results add support to the hypothesis that PdLF contractility becomes decreased and contributes to disease progression in PD.
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Affiliation(s)
- Andrew C Tamashunas
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Aditya Katiyar
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas, USA
| | - Qiao Zhang
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Purboja Purkayastha
- Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA
| | - Pankaj K Singh
- GCC Center for Advanced Microscopy and Image Informatics, Houston, Texas, USA.,Center for Translational Cancer Research, Texas A&M University, Houston, Texas, USA
| | - Sasanka S Chukkapalli
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, Florida, USA.,Center for Molecular Microbiology, University of Florida, Gainesville, Florida, USA
| | - Tanmay P Lele
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas, USA.,Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA.,Department of Translational Medical Sciences, Texas A&M University, College Station, Texas, USA
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44
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Aveic S, Craveiro RB, Wolf M, Fischer H. Current Trends in In Vitro Modeling to Mimic Cellular Crosstalk in Periodontal Tissue. Adv Healthc Mater 2021; 10:e2001269. [PMID: 33191670 PMCID: PMC11469331 DOI: 10.1002/adhm.202001269] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/22/2020] [Indexed: 12/13/2022]
Abstract
Clinical evidence indicates that in physiological and therapeutic conditions a continuous remodeling of the tooth root cementum and the periodontal apparatus is required to maintain tissue strength, to prevent damage, and to secure teeth anchorage. Within the tooth's surrounding tissues, tooth root cementum and the periodontal ligament are the key regulators of a functional tissue homeostasis. While the root cementum anchors the periodontal fibers to the tooth root, the periodontal ligament itself is the key regulator of tissue resorption, the remodeling process, and mechanical signal transduction. Thus, a balanced crosstalk of both tissues is mandatory for maintaining the homeostasis of this complex system. However, the mechanobiological mechanisms that shape the remodeling process and the interaction between the tissues are largely unknown. In recent years, numerous 2D and 3D in vitro models have sought to mimic the physiological and pathophysiological conditions of periodontal tissue. They have been proposed to unravel the underlying nature of the cell-cell and the cell-extracellular matrix interactions. The present review provides an overview of recent in vitro models and relevant biomaterials used to enhance the understanding of periodontal crosstalk and aims to provide a scientific basis for advanced regenerative strategies.
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Affiliation(s)
- Sanja Aveic
- Department of Dental Materials and Biomaterials ResearchRWTH Aachen University HospitalAachen52074Germany
- Neuroblastoma LaboratoryPediatric Research Institute Fondazione Città della SperanzaPadova35127Italy
| | | | - Michael Wolf
- Department of OrthodonticsRWTH Aachen University HospitalAachen52074Germany
| | - Horst Fischer
- Department of Dental Materials and Biomaterials ResearchRWTH Aachen University HospitalAachen52074Germany
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45
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Kuraji R, Wu YH, Hashimoto S, Miyashita Y, Mishiro S, Ito H, Kamarajan P, Kapila Y, Numabe Y. Periodontal inflammation triggers a site-specific and wide radius of calcium metabolic effects on alveolar bone. J Periodontal Res 2020; 56:314-329. [PMID: 33314132 DOI: 10.1111/jre.12824] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 09/30/2020] [Accepted: 10/28/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVE There is a close relationship between inflammation and bone remodeling in the periodontium. However, previous studies have not delineated the alterations in calcium (Ca) metabolism during periodontitis progression. The aim of this current investigation was to examine Ca dynamics in alveolar bone of rats during progression of ligature-induced periodontal inflammation by using 45 Ca, which is an index of hard tissue neogenesis. MATERIAL AND METHODS To induce periodontitis, the maxillary right first molar (M1) of 8-week-old male rats was ligated with a silk suture for 1, 3, 7, and 28 days. The left M1 was not ligated as a control. To evaluate resultant changes in bone neogenesis, 45 CaCl2 was injected intraperitoneally 24 hours before euthanasia. The left-and-right palatal mucosa, molar teeth (M1 and M2), and alveolar bone were harvested for evaluation of 45 Ca radioactivity using a liquid scintillation counter. The distribution of 45 Ca in maxillary tissues was evaluated using autoradiography (ARG). In addition, we analyzed the bone volume fraction (BV/TV) and bone mineral density (BMD) of the alveolar bone by micro-computed tomography. To investigate the number of osteoclasts and osteoblasts, tartrate-resistant acid phosphatase (TRAP) and bone-specific alkaline phosphatase (BAP) were measured by an enzymatic assay and immunohistochemistry, respectively. RESULTS 45 Ca radioactivity in the alveolar bone of the ligature side decreased by 8% compared to the unligated control-side on day 1, whereas on day 7, it markedly increased by 33%. The 45 Ca levels in the gingival tissue and molar teeth were slightly but significantly lower than the control-side on day 1 and higher from day 3 to 28. The variation in 45 Ca levels for the alveolar bone was greater and specific compared with other tissues. Furthermore, on day 7, ARG data revealed that 45 Ca on the control side was primarily localized to the periodontal ligament (PDL) space and alveolar bone crest and barely detected in the gingival tissues and deeper parts of the alveolar bone. On the ligature side, 45 Ca disappeared from the PDL and alveolar crest, but instead was broadly and significantly increased within the deeper zones of the alveolar bone and furcation areas and distant from the site of ligature placement and periodontal inflammation. In the shallow zone of the alveolar bone, these changes in 45 Ca levels on day 7 were consistent with decreases in the bone structural parameters (BV/TV and BMD), enhanced osteoclast presence, and suppressed levels of BAP expression in osteoblasts. In contrast, the deep zone and furcation area showed that TRAP-positive cells increased, but BAP expression was maintained in the resorption lacunae of the alveolar bone. CONCLUSION During periodontitis progression in rats, 45 Ca levels in the alveolar bone exhibited biphasic alterations, namely decreases and increases. These data indicate that periodontitis induces a wide range of site-specific Ca metabolism alterations within the alveolar bone.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Life Science Dentistry, The Nippon Dental University, Tokyo, Japan.,Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan.,Department of Orofacial Sciences, University of California San Francisco, School of Dentistry, San Francisco, CA, USA
| | - Ya-Hsin Wu
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan.,Department of Periodontology, China Medical University Hospital, Taichung City, Taiwan
| | | | - Yukihiro Miyashita
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Saki Mishiro
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Hiroshi Ito
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Pachiyappan Kamarajan
- Department of Orofacial Sciences, University of California San Francisco, School of Dentistry, San Francisco, CA, USA
| | - Yvonne Kapila
- Department of Orofacial Sciences, University of California San Francisco, School of Dentistry, San Francisco, CA, USA
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
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Huang X, Xie M, Xie Y, Mei F, Lu X, Li X, Chen L. The roles of osteocytes in alveolar bone destruction in periodontitis. J Transl Med 2020; 18:479. [PMID: 33308247 PMCID: PMC7733264 DOI: 10.1186/s12967-020-02664-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023] Open
Abstract
Periodontitis, a bacterium-induced inflammatory disease that is characterized by alveolar bone loss, is highly prevalent worldwide. Elucidating the underlying mechanisms of alveolar bone loss in periodontitis is crucial for understanding its pathogenesis. Classically, bone cells, such as osteoclasts, osteoblasts and bone marrow stromal cells, are thought to dominate the development of bone destruction in periodontitis. Recently, osteocytes, the cells embedded in the mineral matrix, have gained attention. This review demonstrates the key contributing role of osteocytes in periodontitis, especially in alveolar bone loss. Osteocytes not only initiate physiological bone remodeling but also assist in inflammation-related changes in bone remodeling. The latest evidence suggests that osteocytes are involved in regulating bone anabolism and catabolism in the progression of periodontitis. The altered secretion of receptor activator of NF-κB ligand (RANKL), sclerostin and Dickkopf-related protein 1 (DKK1) by osteocytes affects the balance of bone resorption and formation and promotes bone loss. In addition, the accumulation of prematurely senescent and apoptotic osteocytes observed in alveolar bone may exacerbate local destruction. Based on their communication with the bloodstream, it is noteworthy that osteocytes may participate in the interaction between local periodontitis lesions and systemic diseases. Overall, further investigations of osteocytes may provide vital insights that improve our understanding of the pathophysiology of periodontitis.
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Affiliation(s)
- Xiaofei Huang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Mengru Xie
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Yanling Xie
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Feng Mei
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Xiaofeng Lu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Xiaoshuang Li
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
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Hirashima S, Ohta K, Kanazawa T, Togo A, Tsuneyoshi R, Kusukawa J, Nakamura KI. Cellular network across cementum and periodontal ligament elucidated by FIB/SEM tomography. ACTA ACUST UNITED AC 2020; 69:53-58. [PMID: 32047915 DOI: 10.1093/jmicro/dfz117] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/25/2019] [Accepted: 12/26/2019] [Indexed: 11/12/2022]
Abstract
Cementocytes in cementum form a lacuna-canalicular network. However, the 3D ultrastructure and range of the cementocyte network are unclear. Here, the 3D ultrastructure of the cementocyte network at the interface between cementum and periodontal ligament (PDL) was investigated on the mesoscale using FIB/SEM tomography. The results revealed a cellular network of cementocytes and PDL cells. A previous histomorphological study revealed the osteocyte-osteoblast-PDL cellular network. We extended this knowledge and revealed the cementum-PDL-bone cellular network, which may orchestrate the remodeling and modification of periodontal tissue, using a suitable method for imaging of complex tissue.
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Affiliation(s)
- Shingo Hirashima
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.,Dental and Oral Medical Center, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Keisuke Ohta
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.,Advanced Imaging Research Center, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Tomonoshin Kanazawa
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Akinobu Togo
- Advanced Imaging Research Center, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Risa Tsuneyoshi
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Jingo Kusukawa
- Dental and Oral Medical Center, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Kei-Ichiro Nakamura
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
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Brodetska L, Natrus L, Lisakovska O, Kaniura O, Iakovenko L, Skrypnyk I, Flis P. The regulatory role of the RANKL/RANK/OPG signaling pathway in the mechanisms of tooth eruption in patients with impacted teeth. BMC Oral Health 2020; 20:261. [PMID: 32948158 PMCID: PMC7501598 DOI: 10.1186/s12903-020-01251-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 09/13/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tooth impaction is a common problem in orthodontic practice and in some cases accompanied by pain and pathological changes of surrounding teeth. Understanding the cellular and molecular mechanisms underlying tooth impaction allows finding the most effective orthodontic treatment for patients with impacted teeth (IT). RANK (receptor activator of NF-κB) / RANKL (RANK ligand) / OPG (osteoprotegerin) signaling pathway controls bone resorption and may be involved in the regulation of tooth eruption. The study aimed to evaluate bone remodeling based on the assessment of the RANKL/RANK/OPG status in patients with IT. METHODS Bone samples from 18 patients (mean age 25.27 ± 3.34) were divided into 3 groups: 1 - bone tissue of healthy persons (control group); 2 - bone tissue, that was taken near the healthy tooth in patients with tooth impaction; 3 - bone tissue, that was collected near the IT. Levels of RANKL, RANK, OPG, osteocalcin (OC), NF-κB p65 subunit, NFATc1, and caspase-3 were determined by western blotting. The difference between groups was assessed using ANOVA followed by Tukey's post-hoc test. P-value ≤0.05 was considered statistically significant. RESULTS We established a 1.73-fold elevation of RANK level in the IT area vs. control, indicating the recruitment of preosteoclasts. An increase in RANKL, OPG, and OC content was demonstrated (1.46-, 1.48-, and 1.42-fold respectively), reflecting the high activity of osteoblasts near the IT. Despite the activation of the RANKL/RANK/OPG system in the impaction area, NF-κB and NFATc1 levels did not change compared vs. control, indicating a blocked/delayed process of osteoclastogenesis. We found a decrease in the content of procaspase-3 (1.28-fold), while the level of its active form p17 increased by 2.26 folds near the healthy tooth in patients with IT compared with control. In the area of IT, we observed an increase in procaspase-3 and p17 levels (1.32 and 1.78 folds). This reflects impairments of caspase-3 activation and accumulation of its inactive form in the IT area that may contribute to the tooth eruption failure. CONCLUSIONS Tooth impaction may be associated with the disturbances in the caspase-3 cascade activation and the imbalance in the RANKL/RANK/OPG system, and as a result, blocked bone resorption.
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Affiliation(s)
- Ludmila Brodetska
- Department of Orthodontics and propaedeutics of Orthopedic Dentistry, Bogomolets National Medical University, Kyiv, Ukraine
| | - Larysa Natrus
- Research Institute of Experimental and Clinical Medicine, Bogomolets National Medical University, Kyiv, Ukraine
| | - Olha Lisakovska
- Department of Biochemistry of Vitamins and Coenzymes, Palladin Institute of Biochemistry, Kyiv, Ukraine.
| | - Olexandr Kaniura
- Department of Orthodontics and propaedeutics of Orthopedic Dentistry, Bogomolets National Medical University, Kyiv, Ukraine
| | - Liudmyla Iakovenko
- Department of maxillofacial surgery of childhood, Bogomolets National Medical University, Kyiv, Ukraine
| | - Irina Skrypnyk
- Department of Orthodontics and propaedeutics of Orthopedic Dentistry, Bogomolets National Medical University, Kyiv, Ukraine
| | - Petro Flis
- Department of Orthodontics and propaedeutics of Orthopedic Dentistry, Bogomolets National Medical University, Kyiv, Ukraine
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Sadowsky SJ, Brunski JB. Are teeth superior to implants? A mapping review. J Prosthet Dent 2020; 126:181-187. [PMID: 32862999 DOI: 10.1016/j.prosdent.2020.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/27/2020] [Accepted: 07/27/2020] [Indexed: 10/23/2022]
Abstract
STATEMENT OF PROBLEM There is a long-held assumption that teeth are superior to implants because the periodontal ligament (PDL) confers a preeminent defense against biologic and mechanical challenges. However, adequate analysis of the literature is lacking. As a result, differential treatment planning of tooth- and implant-supported restorations has been compromised. PURPOSE Given an abundance and diversity of research, the purpose of this mapping review was to identify basic scientific gaps in the knowledge of how teeth and implants respond to biologic and mechanical loads. The findings will offer enhanced evidence-based clinical decision-making when considering replacement of periodontally compromised teeth and the design of implant prostheses. MATERIAL AND METHODS The online databases PubMed, Science Direct, and Web of Science were searched. Published work from 1965 to 2020 was collected and independently analyzed by both authors for inclusion in this review. RESULTS A total of 108 articles met the inclusion criteria of clinical, in vivo, and in vitro studies in the English language on the periradicular and peri-implant bone response to biologic and mechanical loads. The qualitative analysis found that the PDL's enhanced vascularity, stem cell ability, and resident cells that respond to inflammation allow for a more robust defense against biologic threats compared with implants. While the suspensory PDL acts to mediate moderate loads to the bone, higher compressive stress and strain within the PDL itself can initiate a biologic sequence of osteoclastic activity that can affect changes in the adjacent bone. Conversely, the peri-implant bone is more resistant to similar loads and the threshold for overload is higher because of the absence of a stress or strain sensitivity inherent in the PDL. CONCLUSIONS Based on this mapping review, teeth are superior to implants in their ability to resist biologic challenges, but implants are superior to teeth in managing higher compressive loads without prompting bone resorption.
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Affiliation(s)
- Steven J Sadowsky
- Professor, Preventive and Restorative Department, University of the Pacific Arthur A. Dugoni School of Dentistry, San Francisco, Calif.
| | - John B Brunski
- Professor, Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, Calif
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Spitz A, Christovam IO, Marañón-Vásquez GA, Masterson DF, Adesse D, Maia LC, Bolognese AM. Global gene expression profile of periodontal ligament cells submitted to mechanical loading: A systematic review. Arch Oral Biol 2020; 118:104884. [PMID: 32877888 DOI: 10.1016/j.archoralbio.2020.104884] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the evidence reporting gene expression array data of human in vitro cultured periodontal ligament cells (PDLCs) submitted to static mechanical loading compared to a control group. DESIGN Systematic searches were performed in MEDLINE/PubMed, Scopus, Web of Science, Virtual Health Library, The Cochrane Library and the System for Information on Grey Literature in Europe up to June 2019. A narrative synthesis was performed to summarize differentially expressed genes (DEGs). These were grouped according to the culture method (2D or 3D), force type (compression or tension) and observation time. Additionally, gene ontology (GO) analysis was performed using the Database for Annotation Visualization and Integrated Discovery. The risk of bias (RoB) and certainty of evidence (CoE) were assessed using a modified CONSORT checklist and the GRADE tool, respectively. RESULTS Of eight studies included (all rated as having moderate RoB), only two provided the complete list of DEGs and four studies performed GO, gene network or pathways analysis. "Cell proliferation", "cell-cell signaling", "response to hypoxia and to mechanical stimulus" were among the significantly enriched biological processes in 3D-cultured compressed PDLCs (moderate CoE); while "collagen catabolic process", "extracellular matrix organization" and "cell proliferation" were associated with DEGs of 3D-cultured PDLCs submitted to tension (very low CoE). Biological processes significantly enriched in 2D-cultured PDLCs under compression were "extracellular matrix organization", "canonical glycolysis" and "glycolytic process" (very low CoE). CONCLUSION Genes such as NR4A2, NR4A3, NAMPT, PGK1, and REDD1 are suggested as novel biomarkers for orthodontic tooth movement. Limited amount of evidence on the complete gene expression profile and the high heterogeneity in methodologies make it impossible to obtain definite conclusions. New studies following standardized and well-designed in vitro model and reporting complete gene expression datasets are needed.
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Affiliation(s)
- Alice Spitz
- Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, Rua. Prof. Rodolpho Paulo Rocco, 325 - Cidade Universitária da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-617, Brazil.
| | - Ilana Oliveira Christovam
- Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, Rua. Prof. Rodolpho Paulo Rocco, 325 - Cidade Universitária da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-617, Brazil.
| | - Guido Artemio Marañón-Vásquez
- Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, Rua. Prof. Rodolpho Paulo Rocco, 325 - Cidade Universitária da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-617, Brazil.
| | - Daniele Ferreira Masterson
- Central Library of the Health Science Center, Federal University of Rio de Janeiro, Brazil Avenida Carlos Chagas Filho, Bl L, 373 - Cidade Universitária da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-90, Brazil.
| | - Daniel Adesse
- Laboratory of Structural Biology, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil, 4365 - Manguinhos, Rio de Janeiro, RJ, 21040-900, Brazil.
| | - Lucianne Cople Maia
- Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, Rua. Prof. Rodolpho Paulo Rocco, 325 - Cidade Universitária da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-617, Brazil.
| | - Ana Maria Bolognese
- Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, Rua. Prof. Rodolpho Paulo Rocco, 325 - Cidade Universitária da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-617, Brazil.
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