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Tao R, Qiao MQ, Wang B, Fan JP, Gao F, Wang SJ, Guo SY, Xia SL. Laboratory-based Biomarkers for Risk Prediction, Auxiliary Diagnosis and Post-operative Follow-up of Osteoporotic Fractures. Curr Osteoporos Rep 2025; 23:19. [PMID: 40199776 PMCID: PMC11978538 DOI: 10.1007/s11914-025-00914-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/26/2025] [Indexed: 04/10/2025]
Abstract
PURPOSE OF REVIEW Osteoporosis (OP) is characterized by degraded bone microstructure, loss of bone mass and increased risk of fragility fractures. Currently, T-score determined by dual-energy X-ray absorptiometry (DEXA) measurements has been regarded as the gold standard for the diagnosis of osteoporosis. However, multiple factors have indicated that the T-score is insufficient to identify individuals with osteoporosis at a potentially high risk of fracture, or accurately detect those who require treatment, or continuously monitor the risk of re-fracture and clinical outcomes after treatment. This review covers publications in a range of ten years and comprehensively summarizes the studies in laboratory-based biomarkers for osteoporotic fractures (OF), aiming to provide physicians and surgeons with an update of clinical research in identification, verification and application of these tools, and to provide useful information for the design of future clinical studies. RECENT FINDINGS It was found that bone formation markers (such as PINP, BGP, ECM1 and SOST), bone resorption markers (such as β-CTX, TRAcP5b, osteocalcin, RANKL, RANKL/OPG ratio, and t-PINP/β-CTX), hormonal biomarkers (such as IGF- 1, PTH, leptin, adiponectin and AMH), indicators of inflammation and oxidative stress (SII, IL- 6, LTL, FlOP_360, FlOP_400, and GGT), microRNAs (such as miR- 21, miR- 320a- 3p, miR- 491 - 5p, miR- 485 - 3p, miR- 19b- 1- 5p, miR- 203a, miR- 31 - 5p, miR- 502 - 3p, miR- 4739, miR- 497, miR- 19b, and miR- 107), other biomarkers (SAF-AGEs and glycine), adipocytokines (irisin and Omentin- 1), senescence biomarkers (RDW), and lncRNAs (MIAT) may be useful biomarkers for clinical practice. Further validation of these biomarkers and a better understanding of the underlying molecular mechanisms may help in the development and application of these biomarkers for risk prediction of OF, differential diagnosis among OP, OF and healthy individuals, as well as post-operative monitoring of re-fracture risk and treatment outcomes.
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Affiliation(s)
- Rui Tao
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
- Graduate School, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New Area, Shanghai, 201203, China
| | - Mei-Qi Qiao
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
- Graduate School, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New Area, Shanghai, 201203, China
| | - Bin Wang
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
| | - Jian-Pin Fan
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
| | - Feng Gao
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
| | - Shao-Jun Wang
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
| | - Sheng-Yang Guo
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
| | - Sheng-Li Xia
- Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai, 201318, China.
- Graduate School, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New Area, Shanghai, 201203, China.
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Bahrami R, Nikparto N, Gharibpour F, Pourhajibagher M, Bahador A. The effect of light-emitting diode-mediated photobiomodulation therapy on orthodontic tooth movement: A literature review. Photodiagnosis Photodyn Ther 2025; 52:104488. [PMID: 39826598 DOI: 10.1016/j.pdpdt.2025.104488] [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: 12/09/2024] [Revised: 01/10/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
This study aims to review and analyze the impact of light-emitting diode (LED) photobiomodulation (PBM) therapy on orthodontic tooth movement. This non-invasive technique is proposed to reduce time-related side effects, such as white spot lesions, dental caries, and root resorption. Five studies were included in the review, comprising two animal studies (ages 10 and 12 weeks) and three human studies (ages ranging from 15 to 17 years). All studies applied PBM concurrently with force application using sliding mechanics for canine retraction (three studies) and molar protraction (two studies). Two studies employed LEDs with a wavelength of 850 nm, with an exposure time of 5 min daily. Another two studies used LEDs with a wavelength of 618 nm, with an exposure time of 20 min daily. In summary, these studies demonstrated that LED-mediated PBM enhanced orthodontic tooth movement by 33 % (a 1.36-fold increase) compared to the control group. The mean tooth movement per month was 1.55 ± 0.33 mm, which was higher than the control group's average of 1.06 ± 0.35 mm. Also, no studies demonstrated any side effects such as anchorage loss, root resorption, canine rotation, or tooth inclinations. In conclusion, LED-mediated PBM (at wavelengths of 618 nm and 850 nm) can accelerate orthodontic tooth movement without adverse effects, thanks to its biostimulatory properties. Given the advantages of LEDs over traditional lasers-particularly their lower cost and easier application-this method shows promise as a tool to accelerate tooth movement, potentially reducing treatment time and associated side effects.
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Affiliation(s)
- Rashin Bahrami
- Department of Orthodontics, School of Dentistry, Iran University of Medical Sciences, Tehran, Iran
| | | | - Fateme Gharibpour
- Dental Sciences Research Center, Department of Orthodontics, School of Dentistry, Guilan University of Medical Sciences, Rasht, Iran.
| | - Maryam Pourhajibagher
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Abbas Bahador
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Frank JK, Kampleitner C, Heimel P, Leinfellner G, Hanetseder D, Sperger S, Frischer A, Schädl B, Tangl S, Lindner C, Gamauf J, Grillari-Voglauer R, O’Brien FJ, Pultar M, Redl H, Hackl M, Grillari J, Marolt Presen D. Circulating miRNAs are associated with successful bone regeneration. Front Bioeng Biotechnol 2025; 13:1527493. [PMID: 40225119 PMCID: PMC11985807 DOI: 10.3389/fbioe.2025.1527493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/19/2025] [Indexed: 04/15/2025] Open
Abstract
Introduction Bone healing is a well-orchestrated process involving various bone cells and signaling pathways, where disruptions can result in delayed or incomplete healing. MicroRNAs (miRNAs) are small non-coding RNAs capable of influencing various cellular processes, including bone remodeling. Due to their biological relevance and stable presence in biofluids, miRNAs may serve as candidates for diagnosis and prognosis of delayed bone healing. The aim of the study was to investigate changes in miRNAs circulating in the blood during the healing of rat calvaria defects as biomarkers of successful bone regeneration. Methods Standardized calvaria defects were created in 36 Wistar rats with a trephine drill and treated with collagen hydroxyapatite (CHA) scaffolds. The treatment groups included CHA scaffolds only, CHA scaffolds containing a plasmid coding for bone morphogenetic protein 2 (BMP2) and miR-590-5p, CHA scaffolds containing mesenchymal stromal cell-derived extracellular vesicles, and empty defects as a control group. After 1, 4 and 8 weeks of healing, the animals were evaluated by microcomputed tomography (microCT), as well as subjected to histological analyses. Blood was sampled from the tail vein prior to surgeries and after 1, 4, and 8 weeks of healing. miRNAs circulating in the plasma were determined using next-generation sequencing. Results Variability of bone regeneration within the four groups was unexpectedly high and did not result in significant differences between the groups, as indicated by the microCT and histological analyses of the newly formed bone tissue. However, irrespective of the treatment group and regenerative activity, we identified miRNAs with distinct expression patterns of up- and downregulation at different time points. Furthermore, rats with high and low regenerative activity were characterized by distinct circulating miRNA profiles. miR-133-3p was identified as the top upregulated miRNA and miR-375-3p was identified as the top downregulated miRNA in animals exhibiting strong regeneration over all time points evaluated. Conclusion Our study indicates that regardless of the treatment group, success or lack of bone regeneration is associated with a distinct expression pattern of circulating microRNAs. Further research is needed to determine whether their levels in the blood can be used as predictive factors of successful bone regeneration.
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Affiliation(s)
- Julia K. Frank
- Herz Jesu Krankenhaus, Vienna, Austria
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
| | - Carina Kampleitner
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Karl Donath Laboratory for Hard Tissue and Biomaterial Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Patrick Heimel
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Karl Donath Laboratory for Hard Tissue and Biomaterial Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Gabriele Leinfellner
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Dominik Hanetseder
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Simon Sperger
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Amelie Frischer
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Barbara Schädl
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Stefan Tangl
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Karl Donath Laboratory for Hard Tissue and Biomaterial Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Claudia Lindner
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Evercyte GmbH, Vienna, Austria
| | - Johanna Gamauf
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Evercyte GmbH, Vienna, Austria
| | | | - Fergal J O’Brien
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Advanced Materials and Bioengineering Research (AMBER) Centre, Royal College of Surgeons in Ireland & Trinity College Dublin, Dublin, Ireland
| | - Marianne Pultar
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- TAmiRNA GmbH, Vienna, Austria
| | - Heinz Redl
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Matthias Hackl
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- TAmiRNA GmbH, Vienna, Austria
| | - Johannes Grillari
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Institute of Molecular Biotechnology, Department of Biotechnology, BOKU University, Vienna, Austria
| | - Darja Marolt Presen
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Centre for the Technologies of Gene and Cell Therapy, The National Institute of Chemistry, Ljubljana, Slovenia
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Dai G, Jiang W, Feng B, Zhang L. miR-138-5p inhibits healing of femoral fracture osteogenesis in rats by modulating osteoblast differentiation via SIRT1/FOXO1 axis. J Orthop Surg Res 2025; 20:280. [PMID: 40082921 PMCID: PMC11907804 DOI: 10.1186/s13018-025-05667-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/27/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND MicroRNAs have a crucial part to play in maintaining bone formation, signaling, and repair. This research explored the involvement miR-138-5p in modulating osteoblast differentiation in femoral fractures model. METHODS The role of mir-138-5p in the healing process of femoral fractures in rats was assessed through micro computed tomography (CT) imaging. After that, qPCR was employed to identify the cellular mRNA expression levels of miR-138-5p, SIRT1, and FoxO1 in either the callus or MC3T3-E1. Next, the protein expression level of Runx2, OPN, OCN and ALP was determined by western blot or ELISA. A dual-luciferase reporter gene assay was implemented to examine the target of miR-138-5p. The quantity of mineralized nodules was measured by means of alizarin red staining. RESULTS The miR-138-5p inhibitor promotes the mending of femoral fractures. When it is knocked down, the osteogenic differentiation is promoted, which may be caused by the enhanced activity of ALP and the elevation of the expression of Runx2, OPN and OCN. Meanwhile, an increase in the expression of mir-138-5p impairs the biosynthesis of SIRT1 and FoxO1. When SIRT1 and FoxO1 were downregulated with shRNA, the effect caused by the mir-138-5p inhibitor could be reversed. CONCLUSION Our studies uncovered that the overexpressed miR-138-5p might have an inhibitory role in femoral fractures healing by inactivating SIRT1/FOXO1 axis.
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Affiliation(s)
- Guangming Dai
- Department of Hand, Foot and Ankle Surgery, The Third Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, No.20, Shaoxian Road, Kundulun District, Baotou, 014010, P. R. China
| | - Wei Jiang
- Department of Hand, Foot and Ankle Surgery, The Third Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, No.20, Shaoxian Road, Kundulun District, Baotou, 014010, P. R. China
| | - Bo Feng
- Department of Hand, Foot and Ankle Surgery, The Third Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, No.20, Shaoxian Road, Kundulun District, Baotou, 014010, P. R. China
| | - Lan Zhang
- Department of Hand, Foot and Ankle Surgery, The Third Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, No.20, Shaoxian Road, Kundulun District, Baotou, 014010, P. R. China.
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Joris V, Balmayor ER, van Griensven M. miR-125b differentially impacts mineralization in dexamethasone and calcium-treated human mesenchymal stem cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102446. [PMID: 39897583 PMCID: PMC11787018 DOI: 10.1016/j.omtn.2024.102446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 12/31/2024] [Indexed: 02/04/2025]
Abstract
Bone metabolism is highly regulated, and microRNAs (miRs) can contribute to this process. Among them, miR-125b is well known to enhance osteoporosis and reduce osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this work, we aim to evaluate and understand how miR-125b modulates mineralization of hMSCs in two different in vitro models. Cells were cultured in dexamethasone or calcium medium and transfected with miR-125b mimic. Exposure to dexamethasone or calcium medium increased the mineralization of hMSCs and was associated with decreased miR-125b expression. Transfection of miR-125b mimic in dexamethasone-treated cells increased mineralization, while it decreased it in calcium-treated cells. Levels of osteogenic markers presented the same difference. We identified STAT3, p53, and RUNX2 as direct targets of miR-125b in hMSCs. While these targets remained identical in both treatments, their modulation after transfection was different. We showed that miR-125b mimicking differentially modulated the expression of the miR-199a/214 cluster, probably via STAT3/miR-199a/214 and p53/miR-214 pathways. In conclusion, miR-125b affinity for targets implicated in bone remodeling changed depending on the in vitro models used to induce mineralization and led to opposite physiological effects. This work shows the complexity of drugs such as dexamethasone and opens the door for new in vitro models of mineralization.
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Affiliation(s)
- Virginie Joris
- Department of Cell Biology-Inspired Tissue Engineering (cBITE), MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, the Netherlands
| | - Elizabeth R. Balmayor
- Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Martijn van Griensven
- Department of Cell Biology-Inspired Tissue Engineering (cBITE), MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, the Netherlands
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Li LP, Chen XY, Liu HB, Zhu Y, Xie MJ, Li YJ, Luo M, Albahde M, Zhang HY, Lou JY. Oxidative stress-induced circSOD2 inhibits osteogenesis through sponging miR-29b in metabolic-associated fatty liver disease. World J Gastroenterol 2025; 31:98027. [DOI: 10.3748/wjg.v31.i9.98027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 11/24/2024] [Accepted: 01/23/2025] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is characterized by lipid accumulation in hepatocytes and is closely associated with oxidative stress. Increasing clinical evidence indicates that MAFLD is linked to bone metabolic disorders, including osteoporosis. Recent studies indicate that the expression profiles of liver circular RNAs (circRNAs) are altered in MAFLD. However, the effects of these changes on bone metabolism remain poorly understood.
AIM To investigate the effects and mechanism of differently expressed circRNAs secreted by the liver on osteogenic differentiation in MAFLD.
METHODS RNA sequencing was performed to identify highly expressed circRNAs in the liver, validated by quantitative real-time reverse transcription polymerase chain reaction, and localized using fluorescence in situ hybridization (FISH). A mouse model induced by a high-fat diet was used to simulate MAFLD.
RESULTS CircSOD2 was significantly upregulated in liver tissues and primary hepatocytes from subjects with MAFLD. CircSOD2 was induced by oxidative stress and attenuated by antioxidants in the mouse model. In addition, circSOD2 was delivered from hepatocytes to bone marrow mesenchymal stem cells (BMSCs). Furthermore, circSOD2 inhibited the osteogenic differentiation of BMSCs and in vivo bone formation by sponging miR-29b. Moreover, miR-29b inhibition reversed the stimulatory effect of circSOD2 silencing on osteogenic differentiation of BMSCs and in vivo bone formation. Mechanistically, the interaction between circSOD2 and miR-29b confirmed through a luciferase reporter assay and the co-localization in the cytoplasm evidenced by FISH indicated that circSOD2 acted as a sponge for miR-29b.
CONCLUSION This study provides a novel mechanism underlying the liver-bone crosstalk, demonstrating that circSOD2 upregulation in hepatocytes, induced by oxidative stress, inhibits osteogenic differentiation of BMSCs by sponging miR-29b. These findings offer a better understanding of the relationship between MAFLD and osteoporosis.
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Affiliation(s)
- Liang-Ping Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Xiao-Ying Chen
- Department of Emergency Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Hong-Bo Liu
- Department of General Surgery, The People’s Hospital of Songyang, Lishui 323400, Zhejiang Province, China
| | - Yi Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Min-Jie Xie
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Yong-Jian Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Meng Luo
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Mugahed Albahde
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Hong-Yu Zhang
- Department of General Surgery, The People’s Hospital of Songyang, Lishui 323400, Zhejiang Province, China
| | - Jian-Ying Lou
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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Zhu Y, Cheng Q, Liu C, Wang H, Zhu C, Qian J, Hu H, Li B, Guo Q, Shi J. Integrated GelMA and liposome composite hydrogel with effective coupling of angiogenesis and osteogenesis for promoting bone regeneration. Int J Biol Macromol 2025; 297:139835. [PMID: 39824404 DOI: 10.1016/j.ijbiomac.2025.139835] [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: 02/11/2024] [Revised: 12/12/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025]
Abstract
In clinical scenarios, bone defects stemming from trauma, infections, degenerative diseases, or hereditary conditions necessitate considerable bone grafts. Researchers ardently focus on creating diverse biomaterials to expedite and enhance these intricate restorative processes. These biomaterials play a pivotal role in aiding osteogenesis and angiogenesis factors for reconstructing stable, fully developed bone tissue. We observed the utilization of Desferoxamine (DFO) facilitated angiogenesis, thereby enabling Kartogenin (KGN) to activate the β-catenin/Runx-2 pathway. Our study introduces a composite hydrogel loaded with KGN and DFO via liposomes to enhance the coupling of angiogenesis and osteogenesis. Within this composite hydrogel system, KGN and DFO undergo effective release. This controlled release substantially promotes a conducive microenvironment for angiogenesis and osteogenesis. Our in vitro studies provide compelling evidence of the synergistic impact between KGN and DFO on osteogenic processes. Moreover, the composite hydrogel exhibits the capability to enhance the expression of proteins and genes associated with both angiogenesis and osteogenesis. In rat skull defect model, the composite hydrogel notably stimulates vascularization and osteogenic differentiation without infection or mortality. In summary, results underscore the potential of this composite hydrogel as an alternative to autografts for bone defect repair, offering a promising approach for future clinical and regenerative applications.
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Affiliation(s)
- Yuanchen Zhu
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China; Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, PR China
| | - Qi Cheng
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China; Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, PR China
| | - Chengyuan Liu
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China
| | - Huan Wang
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China
| | - Caihong Zhu
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China
| | - Jin Qian
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China; Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, PR China
| | - Hanfeng Hu
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China; Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, PR China
| | - Bin Li
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China.
| | - Qianping Guo
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215000, PR China.
| | - Jinhui Shi
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, PR China.
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Dilawar M, Yu X, Jin Y, Yang J, Lin S, Liao J, Dai Q, Zhang X, Nisar MF, Chen G. Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases. FASEB J 2025; 39:e70417. [PMID: 39985304 DOI: 10.1096/fj.202402545r] [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: 10/21/2024] [Revised: 01/18/2025] [Accepted: 02/14/2025] [Indexed: 02/24/2025]
Abstract
The skeletal system provides vital importance to support organ development and functions. The Notch signaling pathway possesses well-established functions in organ development and cellular homeostasis. The Notch signaling pathway comprises five typical ligands (JAG1, JAG2, DLL1, DLL3, and DLL4), four receptors (Notch1-4), and four intracellular domains (NICD1-4). Each component of the Notch signaling pathway has been demonstrated to be fundamental in osteoblast differentiation and bone formation. The dysregulation in the Notch signaling pathway is highly linked with skeletal disorders or diseases at the developmental and postnatal stages. Recent studies have highlighted the importance of the elements of the Notch signaling pathway in the skeletal system, as well as its interaction with signaling, such as Wnt/β-catenin, BMP, TGF-β, FGF, autophagy, and hedgehog (Hh) to construct a potential gene regulatory network to orchestrate osteogenesis and ossification. Our review has provided a comprehensive summary of the Notch signaling pathway in the skeletal system, as well as the insights targeting Notch signaling for innovative potential drug discovery targets or therapeutic interventions to treat bone disorders, such as osteoporosis and osteoarthritis. An in-depth molecular mechanistic strategy to modulate the Notch signaling pathway and its associated signaling pathway will be encouraged for consideration to trigger enhanced therapeutic approaches for bone disorders by defining Notch-regulating drugs for clinical use.
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Affiliation(s)
- Muhammad Dilawar
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xuan Yu
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yuanyuan Jin
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Jing Yang
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Sisi Lin
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Junguang Liao
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Qi Dai
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xingen Zhang
- Department of Orthopedics, Jiaxing Key Laboratory for Minimally Invasive Surgery in Orthopaedics & Skeletal Regenerative Medicine, Zhejiang Rongjun Hospital, Jiaxing, China
| | - Muhammad Farrukh Nisar
- Department of Physiology & Biochemistry, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
- Ministry of Education and Jiangxi Key Laboratory of Crop Physiology, Ecology and Genetic Breeding, Jiangxi Agricultural University, Nanchang, China
| | - Guiqian Chen
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
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9
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Al-Shibli R, AlSuleimani M, Ahmed I, Al Lawati A, Das S. Association of miRNA and Bone Tumors: Future Therapeutic Inroads. Curr Med Chem 2025; 32:1103-1120. [PMID: 38299295 DOI: 10.2174/0109298673284932231226110754] [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: 09/30/2023] [Revised: 11/24/2023] [Accepted: 11/30/2023] [Indexed: 02/02/2024]
Abstract
Small endogenous non-coding RNA molecules known as micro-ribonucleic acids (miRNAs) control post-transcriptional gene regulation. A change in miRNA expression is related to various diseases, including bone tumors. Benign bone tumors are categorized based on matrix production and predominant cell type. Osteochondromas and giant cell tumors are among the most common bone tumors. Interestingly, miRNAs can function as either tumor suppressor genes or oncogenes, thereby determining the fate of a tumor. In the present review, we discuss various bone tumors with regard to their prognosis, pathogenesis, and diagnosis. The association between miRNAs and bone tumors, such as osteosarcoma, Ewing's sarcoma, chondrosarcoma, and giant-cell tumors, is also discussed. Moreover, miRNA may play an important role in tumor proliferation, growth, and metastasis. Knowledge of the dysregulation, amplification, and deletion of miRNA can be beneficial for the treatment of various bone cancers. The miRNAs could be beneficial for prognosis, treatment, future drug design, and treatment of resistant cases of bone cancer.
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Affiliation(s)
- Rashid Al-Shibli
- Department of Medical, Sultan Qaboos University Hospital, Muscat, 123, Oman
| | | | - Ibrahim Ahmed
- Department of Medical, Sultan Qaboos University Hospital, Muscat, 123, Oman
| | - Abdullah Al Lawati
- Department of Medical, Sultan Qaboos University Hospital, Muscat, 123, Oman
| | - Srijit Das
- Department of Human & Clinical Anatomy, Sultan Qaboos University, Muscat, 123, Oman
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10
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Polizzi A, Alibrandi A, Lo Giudice A, Distefano A, Orlando L, Analazi AM, Pizzo G, Volti GL, Isola G. Impact of periodontal microRNAs associated with alveolar bone remodeling during orthodontic tooth movement: a randomized clinical trial. J Transl Med 2024; 22:1155. [PMID: 39736760 DOI: 10.1186/s12967-024-05933-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: 07/29/2024] [Accepted: 12/01/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND Micro-RNAs (miRNAs) have been reported to play an important role during orthodontic tooth movement (OTM) through the regulation of periodontal soft and hard tissue homeostasis and functions. The aim of the present study was to assess the effects of miRNAs on OTM and to evaluate possible predictors that influenced the overall OTM amount at a 3-month follow-up. METHODS Through a split-mouth design, 21 healthy patients (mean age 13.2 ± 1.8 years) were enrolled in the present study. Clinical parameters and gingival crevicular fluid (GCF) sampling were performed on both compression and tension sides of a random canine to be distalized (test groups) at baseline and at 1 h, 1 day, 1 month and at 3-month after OTM, while the contralateral canine served as a control group. miRNAs - 7a-3p, -7a-2-3p, -7a-5p, -21-3p, -21-5p, -100-3p, -100-5p, -125b-2-3p, -125b-5p, -200b-3p, and - 200b-5p expression was analyzed using a real-time quantitative polymerase chain reaction (RT-PCR). Data were analyzed to assess miRNAs change following OTM. Spearman test, two-way ANOVA and a multivariate regression model were established to evaluate the correlation among miRNAs and clinical parameters and to explore possible predictors of OTM amount at 3-month follow-up. RESULTS At 3-month follow-up, there was an increase of miRNA-7a-2-3p, -21-5p, -100-5p, a decrease of miRNA-125b-5p, 200b-3p and - 200b-5p in the compression side and an increase of miRNA-7a-3p, 100-5p in the tension side (p < 0.05). The two-way ANOVA revealed that OTM determined, on the compression side, a significant upregulation on miRNA-7a-3p (p = 0.017), -7a-2-3p (p = 0.023), -21-5p (p = 0.007), -100-5p (p = 0.025) and a significant downregulation of miRNA-125b-2-3p (p = 0.019) and - 200b-5p (p = 0.017). The multivariate model highlighted that high baseline miRNA-7a2-3p (p = 0.025), -21-5p (p = 0.014), -200b-3p (p = 0.041), young age (p = 0.042), lower bleeding on probing (BOP) (p = 0.021) and miRNA-125b-2-3p (p = 0.021) levels were significant predictors of OTM at 3-month follow-up. CONCLUSIONS In the present study, OTM significantly impacted the expression of the miRNAs analyzed, in both the tension and compression side of traction tooth at 3-month follow-up. High baseline miRNA-7a2-3p, -21-5p, -200b-3p, and lower miRNA-125b-2-3p, together with younger age and lower BOP, were significant predictors of OTM amount at 3-month follow-up. TRIAL REGISTRATION ClinicalTrials.gov NCT06023433 (retrospectively registered).
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Affiliation(s)
- Alessandro Polizzi
- Department of General Surgery and Surgical-Medical Specialties, Unit of Periodontology, School of Dentistry, University of Catania, Via S. Sofia 78, Catania, Catania, 95123, Italy
| | - Angela Alibrandi
- Department of Economics, Unit of Statistical and Mathematical Sciences, University of Messina, Messina, Italy
| | - Antonino Lo Giudice
- Department of General Surgery and Surgical-Medical Specialties, Unit of Periodontology, School of Dentistry, University of Catania, Via S. Sofia 78, Catania, Catania, 95123, Italy
| | - Alfio Distefano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Laura Orlando
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Amer M Analazi
- Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Giuseppe Pizzo
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, 90127, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Gaetano Isola
- Department of General Surgery and Surgical-Medical Specialties, Unit of Periodontology, School of Dentistry, University of Catania, Via S. Sofia 78, Catania, Catania, 95123, Italy.
- International Research Centre on Periodontal, Oral and Sytemic Health "PerioHealth", University of Catania, Catania, Italy.
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11
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Somasundaram S, D F, Genasan K, Kamarul T, Raghavendran HRB. Implications of Biomaterials and Adipose-Derived Stem Cells in the Management of Calvarial Bone Defects. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024. [DOI: 10.1007/s40883-024-00358-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 08/25/2024] [Accepted: 09/13/2024] [Indexed: 01/03/2025]
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12
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Huang H, Chen J, Lin X, Lin Z. Morinda Officinalis Polysaccharides Inhibit Osteoclast Differentiation by Regulating miR-214-3p/NEDD4L in Postmenopausal Osteoporosis Mice. Calcif Tissue Int 2024; 115:673-685. [PMID: 39198270 PMCID: PMC11531433 DOI: 10.1007/s00223-024-01271-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024]
Abstract
To investigate the potential mechanism of Morinda officinalis F. C. How polysaccharides (MOPs) in regulating osteoclast differentiation and apoptosis through miR-214-3p and its target protein. Ovariectomy was performed in 8-week female C57BL6 mice to establish the postmenopausal osteoporosis (PMOP) model. Mice were treated immediately with 500 mg/kg of MOPs (prevention group); others were treated 2 weeks after operation (treatment group). Left femur bone mineral density (BMD) was examined. RAW264.7 cells were administered with receptor activator of NF-κB ligand (RANKL) to establish the osteoclast (OC) model and treated with serum containing 1 or 2 g/kg of MOPs. Apoptosis-related indexes, miR-214-3p, and Expressed Developmentally Down-regulated 4-Like (NEDD4L) were detected by western blot, quantitative real-time-reverse transcription polymerase chain reaction (qRT-PCR), and flow cytometry. OC received a miR-214-3p inhibitor or NEDD4L small interfering RNA (siRNA). MOPs reversed the PMOP-induced changes in bones. Compared with the RANKL group, MOPs increased the apoptosis and related markers in OCs. MOPs decreased the femur miR-214-3p of PMOP mice (P < 0.001). Higher concentrations of MOPs reversed the upregulation of miR-214 mRNA in OCs (P < 0.001). miR-214-3p inhibitor increased the expression of Bax and CC3 (P < 0.01) and decreased the expression of Bcl-2 (P < 0.05). NEDD4L is targeted by miR-214. NEDD4L was upregulated in the RANKL + MOPs group (P < 0.01). miR-214-3p inhibitor increased the upregulation of NEDD4L induced by MOPs (P < 0.05). siRNA NEDD4L significantly reversed the inhibition of MOPs on osteoclast differentiation with miR-214-3p inhibitor (P < 0.01). MOPs effectively prevent PMOP by inhibiting osteoclastogenesis and inducing OC apoptosis through the miR-214-3p/NEDD4L pathway.
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Affiliation(s)
- Hui Huang
- Rehabilitation Department, Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian, China.
| | - Jian Chen
- Xiamen Humanity Rehabilitation Hospital, No. 3775 Xianyue Rd, Xiamen, 361006, China
| | - Xiaomei Lin
- Rehabilitation Department, Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian, China
| | - Zhengkun Lin
- Rehabilitation Department, Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian, China
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13
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Gu C, Tang Q, Li L, Chen Y. Optimization and Implication of Adipose-Derived Stem Cells in Craniofacial Bone Regeneration and Repair. Bioengineering (Basel) 2024; 11:1100. [PMID: 39593759 PMCID: PMC11592193 DOI: 10.3390/bioengineering11111100] [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: 09/14/2024] [Revised: 10/17/2024] [Accepted: 10/27/2024] [Indexed: 11/28/2024] Open
Abstract
Adipose-derived stem cells (ADSCs) have emerged as a promising resource for craniofacial bone regeneration due to their high abundance and easy accessibility, significant osteogenic potential, versatile applications, and potential for personalized medicine, which underscore their importance in this field. This article reviews the current progress of preclinical studies that describe the careful selection of specific ADSC subpopulations, key signaling pathways involved, and usage of various strategies to enhance the osteogenic potential of ADSCs. Additionally, clinical case reports regarding the application of ADSCs in the repair of calvarial defects, cranio-maxillofacial defects, and alveolar bone defects are also discussed.
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Affiliation(s)
- Cong Gu
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
| | - Qinghuang Tang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA
| | - Liwen Li
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Biological Sciences, University at Buffalo, Buffalo, NY 14260, USA
| | - YiPing Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
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14
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Li Q, Wang J, Zhao C. From Genomics to Metabolomics: Molecular Insights into Osteoporosis for Enhanced Diagnostic and Therapeutic Approaches. Biomedicines 2024; 12:2389. [PMID: 39457701 PMCID: PMC11505085 DOI: 10.3390/biomedicines12102389] [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: 09/16/2024] [Revised: 10/16/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Osteoporosis (OP) is a prevalent skeletal disorder characterized by decreased bone mineral density (BMD) and increased fracture risk. The advancements in omics technologies-genomics, transcriptomics, proteomics, and metabolomics-have provided significant insights into the molecular mechanisms driving OP. These technologies offer critical perspectives on genetic predispositions, gene expression regulation, protein signatures, and metabolic alterations, enabling the identification of novel biomarkers for diagnosis and therapeutic targets. This review underscores the potential of these multi-omics approaches to bridge the gap between basic research and clinical applications, paving the way for precision medicine in OP management. By integrating these technologies, researchers can contribute to improved diagnostics, preventative strategies, and treatments for patients suffering from OP and related conditions.
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Affiliation(s)
- Qingmei Li
- Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, China
| | - Jihan Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, China
| | - Congzhe Zhao
- Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, China
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15
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Bojtor B, Balla B, Vaszilko M, Szentpeteri S, Putz Z, Kosa JP, Lakatos P. Genetic Background of Medication-Related Osteonecrosis of the Jaw: Current Evidence and Future Perspectives. Int J Mol Sci 2024; 25:10488. [PMID: 39408816 PMCID: PMC11477157 DOI: 10.3390/ijms251910488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/19/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a rare side effect of antiresorptive drugs that significantly hinders the quality of life of affected patients. The disease develops in the presence of a combination of factors. Important pathogenetic factors include inflammation, inhibition of bone remodeling, or genetic predisposition. Since the first description of this rare side effect in 2003, a growing body of data has suggested a possible role for genetic factors in the disease. Several genes have been suggested to play an important role in the pathogenesis of MRONJ such as SIRT1, VEGFA, and CYP2C8. With the development of molecular biology, newer methods such as miRNA and gene expression studies have been introduced in MRONJ, in addition to methods that can examine the base sequence of the DNA. Describing the complex genetic background of MRONJ can help further understand its pathophysiology as well as identify new therapeutic targets to better manage this adverse drug reaction.
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Affiliation(s)
- Bence Bojtor
- Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary; (B.B.); (Z.P.); (J.P.K.)
| | - Bernadett Balla
- Hungarian Research Network SE-ENDOMOLPAT Research Group, 1085 Budapest, Hungary;
| | - Mihaly Vaszilko
- Department of Oro-Maxillofacial Surgery and Stomatology, Semmelweis University, 1085 Budapest, Hungary; (M.V.); (S.S.)
| | - Szofia Szentpeteri
- Department of Oro-Maxillofacial Surgery and Stomatology, Semmelweis University, 1085 Budapest, Hungary; (M.V.); (S.S.)
| | - Zsuzsanna Putz
- Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary; (B.B.); (Z.P.); (J.P.K.)
- Hungarian Research Network SE-ENDOMOLPAT Research Group, 1085 Budapest, Hungary;
| | - Janos P. Kosa
- Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary; (B.B.); (Z.P.); (J.P.K.)
- Hungarian Research Network SE-ENDOMOLPAT Research Group, 1085 Budapest, Hungary;
| | - Peter Lakatos
- Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary; (B.B.); (Z.P.); (J.P.K.)
- Hungarian Research Network SE-ENDOMOLPAT Research Group, 1085 Budapest, Hungary;
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16
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Fang X, Liu C, Wei K, Shu Z, Zou Y, Zhang Z, Ding Q, Jing S, Li W, Wang T, Li H, Wu H, Liu C, Ma T. Low frequency sinusoidal electromagnetic fields promote the osteogenic differentiation of rat bone marrow mesenchymal stem cells by modulating miR-34b-5p/STAC2. Commun Biol 2024; 7:1156. [PMID: 39284881 PMCID: PMC11405519 DOI: 10.1038/s42003-024-06866-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 09/09/2024] [Indexed: 09/20/2024] Open
Abstract
Electromagnetic fields (EMFs) have emerged as an effective treatment for osteoporosis. However, the specific mechanism underlying their therapeutic efficacy remains controversial. Herein, we confirm the pro-osteogenic effects of 15 Hz and 0.4-1 mT low-frequency sinusoidal EMFs (SEMFs) on rat bone marrow mesenchymal stem cells (BMSCs). Subsequent miRNA sequencing reveal that miR-34b-5p is downregulated in both the 0.4 mT and 1 mT SEMFs-stimulated groups. To clarify the role of miR-34b-5p in osteogenesis, BMSCs are transfected separately with miR-34b-5p mimic and inhibitor. The results indicate that miR-34b-5p mimic transfection suppress osteogenic differentiation, whereas inhibition of miR-34b-5p promote osteogenic differentiation of BMSCs. In vivo assessments using microcomputed tomography, H&E staining, and Masson staining show that miR-34b-5p inhibitor injections alleviate bone mass loss and trabecular microstructure deterioration in ovariectomy (OVX) rats. Further validation demonstrates that miR-34b-5p exerts its effects by regulating STAC2 expression. Modulating the miR-34b-5p/STAC2 axis attenuate the pro-osteogenic effects of low-frequency SEMFs on BMSCs. These studies indicate that the pro-osteogenic effect of SEMFs is partly due to the regulation of the miR-34b-5p/STAC2 pathway, which provides a potential therapeutic candidate for osteoporosis.
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Affiliation(s)
- Xuan Fang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changyu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kang Wei
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zixing Shu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Zou
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zihao Zhang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Ding
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaoze Jing
- Department of Orthopedics, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, China
| | - Weigang Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianqi Wang
- Departments of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hao Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaoxu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Tian Ma
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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17
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Bermúdez M, Martínez-Barajas MG, Bueno-Urquiza LJ, López-Gutiérrez JA, Villegas-Mercado CE, López-Camarillo C. Role of MicroRNA-204 in Regulating the Hallmarks of Breast Cancer: An Update. Cancers (Basel) 2024; 16:2814. [PMID: 39199587 PMCID: PMC11352763 DOI: 10.3390/cancers16162814] [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: 06/24/2024] [Revised: 08/01/2024] [Accepted: 08/09/2024] [Indexed: 09/01/2024] Open
Abstract
microRNA-204-5p (miR-204) is a small noncoding RNA with diverse regulatory roles in breast cancer (BC) development and progression. miR-204 is implicated in the instauration of fundamental traits acquired during the multistep development of BC, known as the hallmarks of cancer. It may act as a potent tumor suppressor by inhibiting key cellular processes like angiogenesis, vasculogenic mimicry, invasion, migration, and metastasis. It achieves this by targeting multiple master genes involved in these processes, including HIF-1α, β-catenin, VEGFA, TGFBR2, FAK, FOXA1, among others. Additionally, miR-204 modulates signaling pathways like PI3K/AKT and interacts with HOTAIR and DSCAM-AS1 lncRNAs, further influencing tumor progression. Beyond its direct effects on tumor cells, miR-204 shapes the tumor microenvironment by regulating immune cell infiltration, suppressing pro-tumorigenic cytokine production, and potentially influencing immunotherapy response. Moreover, miR-204 plays a crucial role in metabolic reprogramming by directly suppressing metabolic genes within tumor cells, indirectly affecting metabolism through exosome signaling, and remodeling metabolic flux within the tumor microenvironment. This review aims to present an update on the current knowledge regarding the role of miR-204 in the hallmarks of BC. In conclusion, miR-204 is a potential therapeutic target and prognostic marker in BC, emphasizing the need for further research to fully elucidate its complex roles in orchestrating aggressive BC behavior.
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Affiliation(s)
- Mercedes Bermúdez
- Faculty of Dentistry, Autonomous University of Chihuahua, Chihuahua 31000, Mexico;
| | | | - Lesly Jazmín Bueno-Urquiza
- University Center for Health Sciences, University of Guadalajara, Guadalajara 44340, Mexico; (M.G.M.-B.); (L.J.B.-U.)
| | - Jorge Armando López-Gutiérrez
- Faculty of Dentistry, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan 80013, Mexico;
| | | | - César López-Camarillo
- Genomic Sciences Program, Autonomous University of Mexico City, San Lorenzo 290, Col del Valle, Mexico City 03100, Mexico
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18
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Shrestha S, Tieu T, Wojnilowicz M, Voelcker NH, Forsythe JS, Frith JE. Delivery of miRNAs Using Porous Silicon Nanoparticles Incorporated into 3D Hydrogels Enhances MSC Osteogenesis by Modulation of Fatty Acid Signaling and Silicon Degradation. Adv Healthc Mater 2024; 13:e2400171. [PMID: 38657207 DOI: 10.1002/adhm.202400171] [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: 01/16/2024] [Revised: 04/10/2024] [Indexed: 04/26/2024]
Abstract
Strategies incorporating mesenchymal stromal cells (MSC), hydrogels and osteoinductive signals offer promise for bone repair. Osteoinductive signals such as growth factors face challenges in clinical translation due to their high cost, low stability and immunogenicity leading to interest in microRNAs as a simple, inexpensive and powerful alternative. The selection of appropriate miRNA candidates and their efficient delivery must be optimised to make this a reality. This study evaluated pro-osteogenic miRNAs and used porous silicon nanoparticles modified with polyamidoamine dendrimers (PAMAM-pSiNP) to deliver these to MSC encapsulated within gelatin-PEG hydrogels. miR-29b-3p, miR-101-3p and miR-125b-5p are strongly pro-osteogenic and are shown to target FASN and ELOVL4 in the fatty acid biosynthesis pathway to modulate MSC osteogenesis. Hydrogel delivery of miRNA:PAMAM-pSiNP complexes enhanced transfection compared to 2D. The osteogenic potential of hBMSC in hydrogels with miR125b:PAMAM-pSiNP complexes is evaluated. Importantly, a dual-effect on osteogenesis occurred, with miRNAs increasing expression of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (RUNX2) whilst the pSiNPs enhanced mineralisation, likely via degradation into silicic acid. Overall, this work presents insights into the role of miRNAs and fatty acid signalling in osteogenesis, providing future targets to improve bone formation and a promising system to enhance bone tissue engineering.
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Affiliation(s)
- Surakshya Shrestha
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
| | - Terence Tieu
- Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing, Bayview Avenue, Clayton, VIC, 3168, Australia
| | - Marcin Wojnilowicz
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing, Bayview Avenue, Clayton, VIC, 3168, Australia
| | - Nicolas H Voelcker
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
- Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing, Bayview Avenue, Clayton, VIC, 3168, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Monash University, Clayton, VIC, 3800, Australia
| | - John S Forsythe
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Monash University, Clayton, VIC, 3800, Australia
| | - Jessica E Frith
- Department of Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Monash University, Clayton, VIC, 3800, Australia
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, 3800, Australia
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19
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Yi X, Leng P, Wang S, Liu L, Xie B. Functional Nanomaterials for the Treatment of Osteoarthritis. Int J Nanomedicine 2024; 19:6731-6756. [PMID: 38979531 PMCID: PMC11230134 DOI: 10.2147/ijn.s465243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 06/15/2024] [Indexed: 07/10/2024] Open
Abstract
Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 595 million people worldwide. Nanomaterials possess superior physicochemical properties and can influence pathological processes due to their unique structural features, such as size, surface interface, and photoelectromagnetic thermal effects. Unlike traditional OA treatments, which suffer from short half-life, low stability, poor bioavailability, and high systemic toxicity, nanotherapeutic strategies for OA offer longer half-life, enhanced targeting, improved bioavailability, and reduced systemic toxicity. These advantages effectively address the limitations of traditional therapies. This review aims to inspire researchers to develop more multifunctional nanomaterials and promote their practical application in OA treatment.
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Affiliation(s)
- Xinyue Yi
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, People’s Republic of China
| | - Pengyuan Leng
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China
| | - Supeng Wang
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, People’s Republic of China
| | - Liangle Liu
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China
| | - Bingju Xie
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China
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20
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Sun J, Chen X, Lin Y, Cai X. MicroRNA-29c-tetrahedral framework nucleic acids: Towards osteogenic differentiation of mesenchymal stem cells and bone regeneration in critical-sized calvarial defects. Cell Prolif 2024; 57:e13624. [PMID: 38414296 PMCID: PMC11216942 DOI: 10.1111/cpr.13624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/29/2024] Open
Abstract
Certain miRNAs, notably miR29c, demonstrate a remarkable capacity to regulate cellular osteogenic differentiation. However, their application in tissue regeneration is hampered by their inherent instability and susceptibility to degradation. In this study, we developed a novel miR29c delivery system utilising tetrahedral framework nucleic acids (tFNAs), aiming to enhance its stability and endocytosis capability, augment the efficacy of miR29c, foster osteogenesis in bone marrow mesenchymal stem cells (BMSCs), and significantly improve the repair of critical-sized bone defects (CSBDs). We confirmed the successful synthesis and biocompatibility of sticky ends-modified tFNAs (stFNAs) and miR29c-modified stFNAs (stFNAs-miR29c) through polyacrylamide gel electrophoresis, microscopy scanning, a cell counting kit-8 assay and so on. The mechanism and osteogenesis effects of stFNAs-miR29c were explored using immunofluorescence staining, western blotting, and reserve transcription quantitative real-time polymerase chain reaction. Additionally, the impact of stFNAs-miR29c on CSBD repair was assessed via micro-CT and histological staining. The nano-carrier, stFNAs-miR29c was successfully synthesised and exhibited exemplary biocompatibility. This nano-nucleic acid material significantly upregulated osteogenic differentiation-related markers in BMSCs. After 2 months, stFNAs-miR29c demonstrated significant bone regeneration and reconstruction in CSBDs. Mechanistically, stFNAs-miR29c enhanced osteogenesis of BMSCs by upregulating the Wnt signalling pathway, contributing to improved bone tissue regeneration. The development of this novel nucleic acid nano-carrier, stFNAs-miR29c, presents a potential new avenue for guided bone regeneration and bone tissue engineering research.
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Affiliation(s)
- Jiafei Sun
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduChina
- Sichuan Provincial Engineering Research Center of Oral BiomaterialsChengduSichuanChina
| | - Xingyu Chen
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduChina
- Sichuan Provincial Engineering Research Center of Oral BiomaterialsChengduSichuanChina
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduChina
- Sichuan Provincial Engineering Research Center of Oral BiomaterialsChengduSichuanChina
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduChina
- Sichuan Provincial Engineering Research Center of Oral BiomaterialsChengduSichuanChina
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21
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Wang T, Nakata H, Shen B, Jiao Z, Yokota K, Kuroda S, Kasugai S, Marukawa E. Involvement of miR-199a-5p-loaded mesoporous silica nanoparticle-polyethyleneimine-KALA in osteogenic differentiation. J Dent Sci 2024; 19:1506-1514. [PMID: 39035341 PMCID: PMC11259637 DOI: 10.1016/j.jds.2024.01.007] [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: 12/24/2023] [Revised: 01/08/2024] [Indexed: 07/23/2024] Open
Abstract
Background/purpose While there are numerous reports on surgical techniques and materials for bone grafting, limited methods are available to enhance the body's inherent capacity to heal bones. Here we investigated microRNA-199a (miR-199a), a molecular that promotes osteoblast differentiation and bone healing. Materials and methods To construct a miR-199a delivery complex, miR-199a-5p mimics were coated with mesoporous silica nanoparticles (MSNs) following modified with polyethyleneimine (PEI) and peptide WEAKLAKALAKALAKHLAKALAKALKACEA (KALA) to obtain 199a-5p-loaded MSN-PEI-KALA. Nanoparticle complexes are assessed for particle size and zeta potential using transmission electron microscopy and dynamic light scattering. Then MC3T3-E1 cells are exposed to MSN_miR-199a-5p @PEI-KALA. The impact of MSN_miR-199a-5p@PEI-KALA at varying concentrations on cell viability is assessed using Cell Counting Kit-8. Cell uptake and distribution were analyzed by double fluorescent staining with fluorescein amidite-labeled MSN_miR-199a@PEI-KALA and lysosome labeling. On day 7 after osteogenic induction, alkaline phosphatase (ALP) staining was conducted. Results The findings indicated that the nanoparticle complexes encapsulating PEI and peptide exhibited an augmentation in both particle size and zeta potential. At a dosage of 10 μg/mL, MSN_miR-199a@PEI-KALA displayed the lowest cytotoxicity compared to the control group. MC3T3-E1 cells treated with MSN_miR-199a-5p@PEI-KALA exhibited intensified ALP staining and elevated mRNA expression levels of ALP, runt-related transcription factor 2, and osteopontin, suggesting the involvement of miR-199a-5p-loaded MSN-PEI-KALA in osteogenic differentiation. Conclusion The successful construction of the delivering complex MSN_miR-199a@PEI-KALA in present research highlights the promise of this biomaterial carrier for the application of miRNAs in treating bone defects.
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Affiliation(s)
- Tianyue Wang
- Department of Oral Implantology and Regenerative Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Regenerative and Reconstructive Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hidemi Nakata
- Department of Oral Implantology and Regenerative Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Regenerative and Reconstructive Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Bing Shen
- Department of Physiology, School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Ziying Jiao
- Department of Physiology, School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Kaori Yokota
- Department of Oral Implantology and Regenerative Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Regenerative and Reconstructive Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Kuroda
- Department of Oral Implantology and Regenerative Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Regenerative and Reconstructive Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Improvement of Gnatho-oral Function, Department of Stomatognathic, Faculty of Dental Medicine, Hokkaido University, Hokkaido, Japan
| | - Shohei Kasugai
- Department of Oral Implantology and Regenerative Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Regenerative and Reconstructive Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Dental Clinic, Southern TOHOKU General Hospital, Fukushima, Japan
| | - Eriko Marukawa
- Department of Regenerative and Reconstructive Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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22
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Gu L, Huang R, Ni N, Zhou R, Su Y, Gu P, Zhang D, Fan X. Mg-Cross-Linked Alginate Hydrogel Induces BMSC/Macrophage Crosstalk to Enhance Bone Tissue Regeneration via Dual Promotion of the Ligand-Receptor Pairing of the OSM/miR-370-3p-gp130 Signaling Pathway. ACS APPLIED MATERIALS & INTERFACES 2024; 16:30685-30702. [PMID: 38859670 DOI: 10.1021/acsami.4c02795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2024]
Abstract
Macrophages play a pivotal role in the crosstalk between the immune and skeletal systems, while Mg-based biomaterials demonstrate immunomodulatory capabilities in this procedure. However, the mechanism of how Mg2+ promotes osteogenesis through the interplay of bone marrow-derived mesenchymal stem cells (BMSCs) and macrophages remains undescribed. Here, we demonstrated that a Mg-cross-linked alginate hydrogel exerted a dual enhancement of BMSCs osteogenic differentiation through the ligand-receptor pairing of the OSM/miR-370-3p-gp130 axis. On the one hand, Mg2+, released from the Mg-cross-linked hydrogel, stimulates bone marrow-derived macrophages to produce and secrete more OSM. On the other hand, Mg2+ lowers the miR-370-3p level in BMSCs and in turn, reverses its suppression on gp130. Then, the OSM binds to the gp130 heterodimer receptor and activates intracellular osteogenic programs in BMSCs. Taken together, this study reveals a novel cross-talk pattern between the skeletal and immune systems under Mg2+ stimulation. This study not only brings new insights into the immunomodulatory properties of Mg-based biomaterials for orthopedic applications but also enriches the miRNA regulatory network and provides a promising target to facilitate bone regeneration in large bone defects.
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Affiliation(s)
- Li Gu
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Rui Huang
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Ni Ni
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Rong Zhou
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yun Su
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Ping Gu
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Dandan Zhang
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Xianqun Fan
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
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23
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Wang M, Xie Z, Yan K, Qiao C, Yan S, Wu G. Identification of the miRNA-mRNA regulatory network in a mouse model of early fracture. Front Genet 2024; 15:1408404. [PMID: 38919952 PMCID: PMC11196604 DOI: 10.3389/fgene.2024.1408404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/13/2024] [Indexed: 06/27/2024] Open
Abstract
Fracture healing is a complex process that involves multiple molecular events, and the regulation mechanism is not fully understood. We acquired miRNA and mRNA transcriptomes of mouse fractures from the Gene Expression Omnibus database (GSE76197 and GSE192542) and integrated the miRNAs and genes that were differentially expressed in the control and fracture groups to construct regulatory networks. There were 130 differentially expressed miRNAs and 4,819 differentially expressed genes, including 72 upregulated and 58 downregulated miRNAs, along with 2,855 upregulated and 1964 downregulated genes during early fracture healing. Gene ontology analysis revealed that most of the differentially expressed genes were enriched in the extracellular matrix (ECM) structure and the ECM organization. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment suggested cell cycle, DNA replication, and mismatch repair were involved in the progression of fracture healing. Furthermore, we constructed a molecular network of miRNAs and mRNAs with inverse expression patterns to elucidate the molecular basis of miRNA-mRNA regulation in fractures. The regulatory network highlighted the potential targets, which may help to provide a mechanistic basis for therapies to improve fracture patient outcomes.
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Affiliation(s)
- Maochun Wang
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | | | | | | | | | - Guoping Wu
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
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24
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Della Bella E, Menzel U, Naros A, Kubosch EJ, Alini M, Stoddart MJ. Identification of circulating miRNAs as fracture-related biomarkers. PLoS One 2024; 19:e0303035. [PMID: 38820355 PMCID: PMC11142570 DOI: 10.1371/journal.pone.0303035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 04/16/2024] [Indexed: 06/02/2024] Open
Abstract
Fracture non-unions affect many patients worldwide, however, known risk factors alone do not predict individual risk. The identification of novel biomarkers is crucial for early diagnosis and timely patient treatment. This study focused on the identification of microRNA (miRNA) related to the process of fracture healing. Serum of fracture patients and healthy volunteers was screened by RNA sequencing to identify differentially expressed miRNA at various times after injury. The results were correlated to miRNA in the conditioned medium of human bone marrow mesenchymal stromal cells (BMSCs) during in vitro osteogenic differentiation. hsa-miR-1246, hsa-miR-335-5p, and miR-193a-5p were identified both in vitro and in fracture patients and their functional role in direct BMSC osteogenic differentiation was assessed. The results showed no influence of the downregulation of the three miRNAs during in vitro osteogenesis. However, miR-1246 may be involved in cell proliferation and recruitment of progenitor cells. Further studies should be performed to assess the role of these miRNA in other processes relevant to fracture healing.
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Affiliation(s)
| | - Ursula Menzel
- AO Research Institute Davos, Davos Platz, Switzerland
| | - Andreas Naros
- AO Research Institute Davos, Davos Platz, Switzerland
- Department of Oral and Maxillofacial Surgery, Tübingen University Hospital, Tübingen, Germany
| | - Eva Johanna Kubosch
- Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Mauro Alini
- AO Research Institute Davos, Davos Platz, Switzerland
| | - Martin J. Stoddart
- AO Research Institute Davos, Davos Platz, Switzerland
- Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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25
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Daamouch S, Blüher M, Vázquez DC, Hackl M, Hofbauer LC, Rauner M. MiR-144-5p and miR-21-5p do not drive bone disease in a mouse model of type 1 diabetes mellitus. JBMR Plus 2024; 8:ziae036. [PMID: 38606150 PMCID: PMC11008730 DOI: 10.1093/jbmrpl/ziae036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 04/13/2024] Open
Abstract
The increased risk of fractures in patients with type 1 diabetes mellitus (T1DM) is nowadays well recognized. However, the exact mechanism of action of diabetic bone disease has not been fully elucidated. MicroRNAs (miRNAs) are gene regulators that operate post-transcriptionally and have been implicated in the development of various metabolic disorders including T1DM. Previous studies have implicated a role for miR-144-5p and miR-21-5p, which are involved in controlling oxidative stress by targeting Nrf2, in T1DM. To date, it is unclear whether miR-144-5p and miR-21-5p affect bone health in T1DM. Thus, this study aimed to investigate the influence of miR-144-5p and miR-21-5p knockdown in the development of bone disease in T1DM male mice. Therefore, T1DM was induced in 10-wk-old male mice using streptozotocin (STZ). One week later, after development of hyperglycemia, antagomir-144-5p and antagomir-21-5p or their non-targeting control were administered at 10 mg/kg BW once a week until the end of the experiment. At 14 wk of age, glucose levels, bone, and fat mass were analyzed. The results revealed that treating T1DM male mice with antagomir-144-5p and antagomir-21-5p did not protect against diabetes development or bone loss, despite the successful downregulation of the miRNAs and the normalization of Nrf2 mRNA levels in bone tissue. Histological and serological parameters of bone formation or resorption were not altered by the antagomir treatment. Finally, we measured the expression of miRNA-144-5p or miRNA-21-5p in the serum of 30 individuals with T1DM and compared them to non-diabetic controls, but did not find an altered expression of either miRNA. In conclusion, the knockdown of miR-144-5p and miR-21-5p does not affect STZ-induced diabetes development or loss of bone mass in male mice. However, it does normalize expression of the anti-oxidant factor Nrf2 in diabetic bone tissue.
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Affiliation(s)
- Souad Daamouch
- Department of Medicine III, Center for Healthy Aging, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Saxony, 04109, Germany
| | | | | | - Lorenz C Hofbauer
- Department of Medicine III, Center for Healthy Aging, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
| | - Martina Rauner
- Department of Medicine III, Center for Healthy Aging, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
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26
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Fu J, Liu J, Zou X, Deng M, Liu G, Sun B, Guo Y, Liu D, Li Y. Transcriptome analysis of mRNA and miRNA in the development of LeiZhou goat muscles. Sci Rep 2024; 14:9858. [PMID: 38684760 PMCID: PMC11058254 DOI: 10.1038/s41598-024-60521-9] [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: 01/02/2024] [Accepted: 04/24/2024] [Indexed: 05/02/2024] Open
Abstract
The progression of muscle development is a pivotal aspect of animal ontogenesis, where miRNA and mRNA exert substantial influence as prominent players. It is important to understand the molecular mechanisms involved in skeletal muscle development to enhance the quality and yield of meat produced by Leizhou goats. We employed RNA sequencing (RNA-SEQ) technology to generate miRNA-mRNA profiles in Leizhou goats, capturing their developmental progression at 0, 3, and 6 months of age. A total of 977 mRNAs and 174 miRNAs were found to be differentially expressed based on our analysis. Metabolic pathways, calcium signaling pathways, and amino acid synthesis and metabolism were found to be significantly enriched among the differentially expressed mRNA in the enrichment analysis. Meanwhile, we found that among these differentially expressed mRNA, some may be related to muscle development, such as MYL10, RYR3, and CSRP3. Additionally,, we identified five muscle-specific miRNAs (miR-127-3p, miR-133a-3p, miR-193b-3p, miR-365-3p, and miR-381) that consistently exhibited high expression levels across all three stages. These miRNAs work with their target genes (FHL3, SESN1, PACSIN3, LMCD1) to regulate muscle development. Taken together, our findings suggest that several miRNAs and mRNAs are involved in regulating muscle development and cell growth in goats. By uncovering the molecular mechanisms involved in muscle growth and development, these findings contribute valuable knowledge that can inform breeding strategies aimed at enhancing meat yield and quality in Leizhou goats.
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Affiliation(s)
- Junjie Fu
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, 510642, China
| | - Jie Liu
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, 510640, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, 510642, China
| | - Xian Zou
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, 510640, China
| | - Ming Deng
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, 510642, China
| | - Guangbin Liu
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, 510642, China
| | - Baoli Sun
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, 510642, China
| | - Yongqing Guo
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, 510642, China
| | - Dewu Liu
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, 510642, China
| | - Yaokun Li
- College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
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27
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Daponte V, Henke K, Drissi H. Current perspectives on the multiple roles of osteoclasts: Mechanisms of osteoclast-osteoblast communication and potential clinical implications. eLife 2024; 13:e95083. [PMID: 38591777 PMCID: PMC11003748 DOI: 10.7554/elife.95083] [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: 12/14/2023] [Accepted: 03/29/2024] [Indexed: 04/10/2024] Open
Abstract
Bone remodeling is a complex process involving the coordinated actions of osteoblasts and osteoclasts to maintain bone homeostasis. While the influence of osteoblasts on osteoclast differentiation is well established, the reciprocal regulation of osteoblasts by osteoclasts has long remained enigmatic. In the past few years, a fascinating new role for osteoclasts has been unveiled in promoting bone formation and facilitating osteoblast migration to the remodeling sites through a number of different mechanisms, including the release of factors from the bone matrix following bone resorption and direct cell-cell interactions. Additionally, considerable evidence has shown that osteoclasts can secrete coupling factors known as clastokines, emphasizing the crucial role of these cells in maintaining bone homeostasis. Due to their osteoprotective function, clastokines hold great promise as potential therapeutic targets for bone diseases. However, despite long-standing work to uncover new clastokines and their effect in vivo, more substantial efforts are still required to decipher the mechanisms and pathways behind their activity in order to translate them into therapies. This comprehensive review provides insights into our evolving understanding of the osteoclast function, highlights the significance of clastokines in bone remodeling, and explores their potential as treatments for bone diseases suggesting future directions for the field.
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Affiliation(s)
- Valentina Daponte
- Department of Orthopaedics, Emory University School of MedicineAtlantaUnited States
- VA Medical CenterAtlantaUnited States
| | - Katrin Henke
- Department of Orthopaedics, Emory University School of MedicineAtlantaUnited States
| | - Hicham Drissi
- Department of Orthopaedics, Emory University School of MedicineAtlantaUnited States
- VA Medical CenterAtlantaUnited States
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28
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Dashti P, Lewallen EA, Gordon JAR, Montecino MA, Davie JR, Stein GS, van Leeuwen JPTM, van der Eerden BCJ, van Wijnen AJ. Epigenetic regulators controlling osteogenic lineage commitment and bone formation. Bone 2024; 181:117043. [PMID: 38341164 DOI: 10.1016/j.bone.2024.117043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/08/2024] [Accepted: 02/04/2024] [Indexed: 02/12/2024]
Abstract
Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related gene expression is controlled by nucleosome-based chromatin architecture that limits the accessibility of lineage-specific gene regulatory DNA sequences and sequence-specific transcription factors. From a developmental perspective, bone-specific gene expression must be suppressed during the early stages of embryogenesis to prevent the premature mineralization of skeletal elements during fetal growth in utero. Hence, bone formation is initially inhibited by gene suppressive epigenetic regulators, while other epigenetic regulators actively support osteoblast differentiation. Prominent epigenetic regulators that stimulate or attenuate osteogenesis include lysine methyl transferases (e.g., EZH2, SMYD2, SUV420H2), lysine deacetylases (e.g., HDAC1, HDAC3, HDAC4, HDAC7, SIRT1, SIRT3), arginine methyl transferases (e.g., PRMT1, PRMT4/CARM1, PRMT5), dioxygenases (e.g., TET2), bromodomain proteins (e.g., BRD2, BRD4) and chromodomain proteins (e.g., CBX1, CBX2, CBX5). This narrative review provides a broad overview of the covalent modifications of DNA and histone proteins that involve hundreds of enzymes that add, read, or delete these epigenetic modifications that are relevant for self-renewal and differentiation of mesenchymal stem cells, skeletal stem cells and osteoblasts during osteogenesis.
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Affiliation(s)
- Parisa Dashti
- Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Eric A Lewallen
- Department of Biological Sciences, Hampton University, Hampton, VA, USA
| | | | - Martin A Montecino
- Institute of Biomedical Sciences, Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Millennium Institute Center for Genome Regulation (CRG), Santiago, Chile
| | - James R Davie
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada; CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada.
| | - Gary S Stein
- Department of Biochemistry, University of Vermont, Burlington, VT, USA
| | | | - Bram C J van der Eerden
- Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, Netherlands.
| | - Andre J van Wijnen
- Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Biochemistry, University of Vermont, Burlington, VT, USA.
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Balachander GM, Nilawar S, Meka SRK, Ghosh LD, Chatterjee K. Unravelling microRNA regulation and miRNA-mRNA regulatory networks in osteogenesis driven by 3D nanotopographical cues. Biomater Sci 2024; 12:978-989. [PMID: 38189225 DOI: 10.1039/d3bm01597a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Three-dimensional (3D) culturing of cells is being adopted for developing tissues for various applications such as mechanistic studies, drug testing, tissue regeneration, and animal-free meat. These approaches often involve cost-effective differentiation of stem or progenitor cells. One approach is to exploit architectural cues on a 3D substrate to drive cellular differentiation, which has been shown to be effective in various studies. Although extensive gene expression data from such studies have shown that gene expression patterns might differ, the gene regulatory networks controlling the expression of genes are rarely studied. In this study, we profiled genes and microRNAs (miRNAs) via next-generation sequencing (NGS) in human mesenchymal stem cells (hMSCs) driven toward osteogenesis via architectural cues in 3D matrices (3D conditions) and compared with cells in two-dimensional (2D) culture driven toward osteogenesis via soluble osteoinductive factors (OF conditions). The total number of differentially expressed genes was smaller in 3D compared to OF conditions. A distinct set of genes was observed under these conditions that have been shown to control osteogenic differentiation via different pathways. Small RNA sequencing revealed a core set of miRNAs to be differentially expressed under these conditions, similar to those that have been previously implicated in osteogenesis. We also observed a distinct regulation of miRNAs in these samples that can modulate gene expression, suggesting supplementary gene regulatory networks operative under different stimuli. This study provides insights into studying gene regulatory networks for identifying critical nodes to target for enhanced cellular differentiation and reveal the differences in physical and biochemical cues to drive cell fates.
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Affiliation(s)
- Gowri Manohari Balachander
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Sagar Nilawar
- Department of Materials Engineering, Indian Institute of Science, Bangalore-560012, India.
| | - Sai Rama Krishna Meka
- Department of Materials Engineering, Indian Institute of Science, Bangalore-560012, India.
| | - Lopamudra Das Ghosh
- Department of Materials Engineering, Indian Institute of Science, Bangalore-560012, India.
| | - Kaushik Chatterjee
- Department of Materials Engineering, Indian Institute of Science, Bangalore-560012, India.
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Wang X, Gong W, Li R, Li L, Wang J. Preparation of genetically or chemically engineered exosomes and their therapeutic effects in bone regeneration and anti-inflammation. Front Bioeng Biotechnol 2024; 12:1329388. [PMID: 38314353 PMCID: PMC10834677 DOI: 10.3389/fbioe.2024.1329388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 01/11/2024] [Indexed: 02/06/2024] Open
Abstract
The treatment of bone or cartilage damage and inflammation-related diseases has been a long-standing research hotspot. Traditional treatments such as surgery and cell therapy have only displayed limited efficacy because they can't avoid potential deterioration and ensure cell activity. Recently, exosomes have become a favorable tool for various tissue reconstruction due to their abundant content of proteins, lipids, DNA, RNA and other substances, which can promote bone regeneration through osteogenesis, angiogenesis and inflammation modulation. Besides, exosomes are also promising delivery systems because of stability in the bloodstream, immune stealth capacity, intrinsic cell-targeting property and outstanding intracellular communication. Despite having great potential in therapeutic delivery, exosomes still show some limitations in clinical studies, such as inefficient targeting ability, low yield and unsatisfactory therapeutic effects. In order to overcome the shortcomings, increasing studies have prepared genetically or chemically engineered exosomes to improve their properties. This review focuses on different methods of preparing genetically or chemically engineered exosomes and the therapeutic effects of engineering exosomes in bone regeneration and anti-inflammation, thereby providing some references for future applications of engineering exosomes.
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Affiliation(s)
- Xinyue Wang
- School of Stomatology, Lanzhou University, Lanzhou, China
| | - Weitao Gong
- School of Stomatology, Lanzhou University, Lanzhou, China
| | - Rongrong Li
- School of Stomatology, Lanzhou University, Lanzhou, China
| | - Lin Li
- School of Stomatology, Lanzhou University, Lanzhou, China
| | - Jing Wang
- School of Stomatology, Lanzhou University, Lanzhou, China
- Clinical Research Center for Oral Diseases, Lanzhou, China
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31
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Daneshian Y, Lewallen EA, Badreldin AA, Dietz AB, Stein GS, Cool SM, Ryoo HM, Cho YD, van Wijnen AJ. Fundamentals and Translational Applications of Stem Cells and Biomaterials in Dental, Oral and Craniofacial Regenerative Medicine. Crit Rev Eukaryot Gene Expr 2024; 34:37-60. [PMID: 38912962 DOI: 10.1615/critreveukaryotgeneexpr.2024053036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/25/2024]
Abstract
Regenerative dental medicine continuously expands to improve treatments for prevalent clinical problems in dental and oral medicine. Stem cell based translational opportunities include regenerative therapies for tooth restoration, root canal therapy, and inflammatory processes (e.g., periodontitis). The potential of regenerative approaches relies on the biological properties of dental stem cells. These and other multipotent somatic mesenchymal stem cell (MSC) types can in principle be applied as either autologous or allogeneic sources in dental procedures. Dental stem cells have distinct developmental origins and biological markers that determine their translational utility. Dental regenerative medicine is supported by mechanistic knowledge of the molecular pathways that regulate dental stem cell growth and differentiation. Cell fate determination and lineage progression of dental stem cells is regulated by multiple cell signaling pathways (e.g., WNTs, BMPs) and epigenetic mechanisms, including DNA modifications, histone modifications, and non-coding RNAs (e.g., miRNAs and lncRNAs). This review also considers a broad range of novel approaches in which stem cells are applied in combination with biopolymers, ceramics, and composite materials, as well as small molecules (agonistic or anti-agonistic ligands) and natural compounds. Materials that mimic the microenvironment of the stem cell niche are also presented. Promising concepts in bone and dental tissue engineering continue to drive innovation in dental and non-dental restorative procedures.
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Affiliation(s)
- Yasaman Daneshian
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Eric A Lewallen
- Department of Biological Sciences, Hampton University, Hampton, VA, USA
| | - Amr A Badreldin
- Laboratory of Molecular Signaling, Division of Oral and Systemic Health Sciences, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA
| | - Allan B Dietz
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Gary S Stein
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT 05405; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT 05405
| | - Simon M Cool
- School of Chemical Engineering, The University of Queensland, Brisbane, Queensland, Australia
| | - Hyun-Mo Ryoo
- School of Dentistry, Seoul National University, 28 Yeonkun-dong, Chongro-gu Seoul, 110-749, Republic of Korea
| | - Young Dan Cho
- Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital, 101 Daehak‑no, Jongno‑gu, Seoul 03080, Republic of Korea
| | - Andre J van Wijnen
- Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA
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Xu M, Song D, Xie X, Qin Y, Huang J, Wang C, Chen J, Su Y, Xu J, Zhao J, Liu Q. CGK733 alleviates ovariectomy-induced bone loss through blocking RANKL-mediated Ca 2+ oscillations and NF-κB/MAPK signaling pathways. iScience 2023; 26:107760. [PMID: 37720109 PMCID: PMC10504545 DOI: 10.1016/j.isci.2023.107760] [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: 05/11/2023] [Revised: 08/20/2023] [Accepted: 08/25/2023] [Indexed: 09/19/2023] Open
Abstract
Osteoporosis is a prevalent systemic metabolic disease in modern society, in which patients often suffer from bone loss due to over-activation of osteoclasts. Currently, amelioration of bone loss through modulation of osteoclast activity is a major therapeutic strategy. Ataxia telangiectasia mutated (ATM) inhibitor CGK733 (CG) was reported to have a sensitizing impact in treating malignancies. However, its effect on osteoporosis remains unclear. In this study, we investigated the effects of CG on osteoclast differentiation and function, as well as the therapeutic effects of CG on osteoporosis. Our study found that CG inhibits osteoclast differentiation and function. We further found that CG inhibits the activation of NFATc1 and ultimately osteoclast formation by inhibiting RANKL-mediated Ca2+ oscillation and the NF-κB/MAPK signaling pathway. Next, we constructed an ovariectomized mouse model and demonstrated that CG improved bone loss in ovariectomized mice. Therefore, CG may be a potential drug for the prevention and treatment of osteoporosis.
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Affiliation(s)
- Minglian Xu
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Dezhi Song
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Xiaoxiao Xie
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yiwu Qin
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Jian Huang
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Chaofeng Wang
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Junchun Chen
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yuangang Su
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Jiake Xu
- School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China
| | - Jinmin Zhao
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Qian Liu
- Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China
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Minbo J, Feng C, Wen H, Jamil M, Zhang H, Abdel-Maksoud MA, Zakri AM, Almanaa TN, Alfuraydi AA, Almunqedhi BM. Up-regulated and hypomethylated genes are causative factors and diagnostic markers of osteoporosis. Am J Transl Res 2023; 15:6042-6057. [PMID: 37969207 PMCID: PMC10641362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 09/25/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND Due to the lack of sensitive diagnostic biomarkers for osteoporosis (OP), there is an urgent need to identify and uncover biomarkers associated with the disease in order to facilitate early clinical diagnosis and effective intervention strategies. METHODS GEO2R was employed to conduct a screening of differentially expressed genes (DEGs) within the transcriptome sequencing data obtained from blood samples of OP patients within the GSE163849 dataset. Subsequently, we conducted expression confirmation of the identified DEGs using an additional dataset, GSE35959. To further explore Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, MicroRNA (miRNA) interactions, and drug predictions, we employed the DAVID, miRTarBase, and DrugBank databases. For validation purposes, clinical OP samples paired with normal controls were collected from the Pakistani population. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to assess the expression levels of DEGs and miRNA, while targeted bisulfite sequencing (bisulfite-seq) analysis was used to investigate methylation patterns. DNA and RNA from clinical OP and normal control samples were extracted using appropriate methods. RESULTS Out of total identified 269 DEGs, EGFR (epidermal growth factor receptor), HMOX1 (heme oxygenase-1), PGR (progesterone receptor), CXCL10 (C-X-C motif chemokine ligand 10), CCL5 (C-C motif chemokine ligand 5), and IL12B (interleukin 12B) were prioritized as top DEGs in OP patients. Expression validation of these genes on additional Gene Expression Omnibus (GEO) dataset and Pakistani OP patients revealed consistent significant up-regulation of these genes in OP patients. Receiver operating characteristic (ROC) analysis demonstrated that these DEGs displayed considerable diagnostic accuracy for detecting OP. Targeted bisulfite-seq analysis further revealed that EGFR, HMOX1, PGR, CXCL10, CCL5, and IL12B were hypomethylated in OP patients. Moreover, has-miR-27a-5p, a common expression regulator of the EGFR, HMOX1, PGR, CXCL10, CCL5, and IL12B was also significantly down-regulated in OP patients. CONCLUSION The DEGs that have been identified hold significant potential for the future development of diagnostic and treatment approaches for OP in preclinical and clinical applications.
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Affiliation(s)
- Jiang Minbo
- Department of Orthopedic, Shanghai Songjiang District Central HospitalShanghai 201699, China
| | - Chen Feng
- Department of Orthopedics, Hongqi HospitalMuDanjiang 157011, Heilongjiang, China
| | - Hongli Wen
- Department of Foreign Language, MuDanjiang Medical UniversityMuDanjiang 157011, Heilongjiang, China
| | - Muhammad Jamil
- PARC Arid Zone Research CenterDera Ismail Khan 29050, Pakistan
| | - Heng Zhang
- Department of Orthopedic, Shanghai Songjiang District Central HospitalShanghai 201699, China
| | - Mostafa A Abdel-Maksoud
- Department of Botany and Microbiology, College of Science, King Saud UniversityP.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Adel M Zakri
- Department of Plant Production, College of Food and Agricultural Sciences, King Saud UniversityRiyadh 11451, Saudi Arabia
| | - Taghreed N Almanaa
- Department of Botany and Microbiology, College of Science, King Saud UniversityP.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Akram A Alfuraydi
- Department of Botany and Microbiology, College of Science, King Saud UniversityP.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Bandar M Almunqedhi
- Department of Botany and Microbiology, College of Science, King Saud UniversityP.O. Box 2455, Riyadh 11451, Saudi Arabia
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Xu K, Mu C, Zhang C, Deng S, Lin S, Zheng L, Chen W, Zhang Q. Antioxidative and antibacterial gallium (III)-phenolic coating for enhanced osseointegration of titanium implants via pro-osteogenesis and inhibiting osteoclastogenesis. Biomaterials 2023; 301:122268. [PMID: 37572468 DOI: 10.1016/j.biomaterials.2023.122268] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/26/2023] [Accepted: 08/06/2023] [Indexed: 08/14/2023]
Abstract
Improving the ability of implants to integrate with natural bone tissue at the initial stage of implantation remains a huge challenge because bone-to-implant interfaces are often accompanied by abnormal microenvironments with infection, reactive oxygen species (ROS) and unbalanced bone homeostasis. In this study, a multifunctional coating was fabricated on the basis of gallium (III)-phenolic networks. It is easily obtained by immersing the implants into a mixed solution of tannic acids (TAs) and gallium ions. The thickness of the coating can be precisely controlled by adjusting the number and time of immersion experiments. The resulting coating displays excellent near-infrared photothermal property. As the coating degrades, TAs and gallium ions with low concentration are released from the coating, which is more rapid in acidic and oxidative stress microenvironments. Photothermal performance as well as released TAs and gallium ions give the coating outstanding broad-spectrum antibacterial ability. Furthermore, the coating effectively reduces intracellular ROS of osteoblasts. In vitro and in vivo experiments demonstrate the capability of the coating enhancing implants' osseointegration via pro-osteogenesis and inhibiting osteoclastogenesis. The findings imply that gallium (III)-phenolic coating holds great promise to promote implant osseointegration by rescuing abnormal microenvironments of infection, oxidative stress and unbalanced bone homeostasis.
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Affiliation(s)
- Kui Xu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, 230038, Anhui, PR China; Institute of Biomedical Engineering, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, Guangdong, PR China; The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, PR China.
| | - Caiyun Mu
- College of Acumox and Tuina, Anhui University of Chinese Medicine, Hefei, 230038, Anhui, PR China
| | - Chi Zhang
- Medical Research Center, Ningbo City First Hospital, Ningbo, Zhejiang, 315010, PR China
| | - Sijie Deng
- Institute of Biomedical Engineering, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, Guangdong, PR China
| | - Shan Lin
- Institute of Biomedical Engineering, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, Guangdong, PR China
| | - Linlin Zheng
- Institute of Biomedical Engineering, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, Guangdong, PR China
| | - Weizhen Chen
- Center of Clinical Laboratory & the Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, PR China.
| | - Qiqing Zhang
- Institute of Biomedical Engineering, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, Guangdong, PR China.
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Li MJ, Liang ZT, Sun Y, Li J, Zhang HQ, Deng A. Research progress on the regulation of bone marrow stem cells by noncoding RNAs in adolescent idiopathic scoliosis. J Cell Physiol 2023; 238:2228-2242. [PMID: 37682901 DOI: 10.1002/jcp.31119] [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: 02/26/2023] [Revised: 08/16/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023]
Abstract
Adolescent idiopathic scoliosis (AIS) is a common spinal deformity in young women, but its pathogenesis remains unclear. The primary pathogenic factors contributing to its development include genetics, abnormal bone metabolism, and endocrine factors. Bone marrow stem cells (BMSCs) play a crucial role in the pathogenesis of AIS by regulating its occurrence and progression. Noncoding RNAs (ncRNAs) are also involved in the pathogenesis of AIS, and their role in regulating BMSCs in patients with AIS requires further evaluation. In this review, we discuss the relevant literature regarding the osteogenic, chondrogenic, and lipogenic differentiation of BMSCs. The corresponding mechanisms of ncRNA-mediated BMSC regulation in patients with AIS, recent advancements in AIS and ncRNA research, and the importance of ncRNA translation profiling and multiomics are highlighted.
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Affiliation(s)
- Meng-Jun Li
- Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Zhuo-Tao Liang
- Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Yang Sun
- Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Jiong Li
- Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Hong-Qi Zhang
- Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Ang Deng
- Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
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Gueguen J, Girard D, Rival B, Fernandez J, Goriot ME, Banzet S. Spinal cord injury dysregulates fibro-adipogenic progenitors miRNAs signaling to promote neurogenic heterotopic ossifications. Commun Biol 2023; 6:932. [PMID: 37700159 PMCID: PMC10497574 DOI: 10.1038/s42003-023-05316-w] [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: 11/18/2022] [Accepted: 09/01/2023] [Indexed: 09/14/2023] Open
Abstract
Neurogenic heterotopic ossifications are intramuscular bone formations developing following central nervous system injury. The pathophysiology is poorly understood and current treatments for this debilitating condition remain unsatisfying. Here we explored the role of miRNAs in a clinically relevant mouse model that combines muscle and spinal cord injury, and in patients' cells. We found an osteo-suppressive miRNAs response in injured muscle that was hindered when the spinal cord injury was associated. In isolated fibro-adipogenic progenitors from damaged muscle (cells at the origin of ossification), spinal cord injury induced a downregulation of osteo-suppressive miRNAs while osteogenic markers were overexpressed. The overexpression of selected miRNAs in patient's fibro-adipogenic progenitors inhibited mineralization and osteo-chondrogenic markers in vitro. Altogether, we highlighted an osteo-suppressive mechanism involving multiple miRNAs in response to muscle injury that prevents osteogenic commitment which is ablated by the neurologic lesion in heterotopic ossification pathogenesis. This provides new research hypotheses for preventive treatments.
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Affiliation(s)
- Jules Gueguen
- Institut de Recherche Biomédicale des Armées, 92140, Clamart, France
- INSERM UMR-MD-1197, 92140, Clamart, France
| | - Dorothée Girard
- Institut de Recherche Biomédicale des Armées, 92140, Clamart, France
- INSERM UMR-MD-1197, 92140, Clamart, France
| | - Bastien Rival
- Institut de Recherche Biomédicale des Armées, 92140, Clamart, France
- INSERM UMR-MD-1197, 92140, Clamart, France
| | - Juliette Fernandez
- Institut de Recherche Biomédicale des Armées, 92140, Clamart, France
- INSERM UMR-MD-1197, 92140, Clamart, France
| | - Marie-Emmanuelle Goriot
- Institut de Recherche Biomédicale des Armées, 92140, Clamart, France
- INSERM UMR-MD-1197, 92140, Clamart, France
| | - Sébastien Banzet
- Institut de Recherche Biomédicale des Armées, 92140, Clamart, France.
- INSERM UMR-MD-1197, 92140, Clamart, France.
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Al-Rawaf HA, Gabr SA, Iqbal A, Alghadir AH. MicroRNAs as potential biopredictors for premenopausal osteoporosis: a biochemical and molecular study. BMC Womens Health 2023; 23:481. [PMID: 37689658 PMCID: PMC10493018 DOI: 10.1186/s12905-023-02626-3] [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: 06/06/2023] [Accepted: 08/29/2023] [Indexed: 09/11/2023] Open
Abstract
BACKGROUND Circulating micro-RNAs have been proposed as a new type of biomarker in several diseases, particularly those related to bone health. They have shown great potential due to their feasibility and simplicity of measurement in all body fluids, especially urine, plasma, and serum. AIM This study aimed to evaluate the expression of a set of mRNAs, namely miR-21, miR-24, mir-100, miR-24a, miR-103-3p, and miR-142-3p. Their proposed roles in the progression of osteoporosis were identified using a real-time polymerase chain reaction (RT-PCR) analysis in premenopausal women. In addition, their correlations with osteocalcin (OC), bone-specific alkaline phosphatase (BAP), and deoxypyridinoline (DPD) bone markers were explored. METHODS A total of 85 healthy premenopausal women aged 25-50 years old were included in this study. Based on a DXA scan (Z-score) analysis and calcaneus broadband ultrasound attenuation scores (c-BUAs), measured via quantitative ultrasound (QUS), the subjects were classified into three groups: normal group (n = 25), osteopenia (n = 30), and osteoporosis (n = 30). Real-time-PCR and immunoassay analyses were performed to determine miRNA expression levels and serum OC, s-BAP, and DPD, respectively, as biomarkers of bone health. RESULTS Among the identified miRNAs, only miR-21, miR-24, and mir-100 were significantly upregulated and increased in the serum of patients with osteopenia and osteoporosis, and miR-24a, miR-103-3p, and miR-142-3p were downregulated and significantly decreased in osteoporosis. Both upregulated and downregulated miRNAs were significantly correlated with BMD, c-BUA, OC, s-BAP, and DPD. CONCLUSION A group of circulating miRNAs was shown to be closely correlated with the parameters BMD, c-BUA, OC, s-BAP, and DPD, which are traditionally used for bone-health measurements. They could be identified as non-invasive biomarkers in premenopausal patients with osteoporosis. More studies with large sample sizes are recommended to estimate the mechanistic role of miRNAs in osteoporosis pathogenesis and to provide evidence for the use of these miRNAs as a non-invasive method of diagnosing clinical osteoporosis, especially in premenopausal patients.
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Affiliation(s)
- Hadeel A. Al-Rawaf
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433 Saudi Arabia
| | - Sami A. Gabr
- Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433 Saudi Arabia
| | - Amir Iqbal
- Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433 Saudi Arabia
| | - Ahmad H. Alghadir
- Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433 Saudi Arabia
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Dalle Carbonare L, Minoia A, Braggio M, Bertacco J, Piritore FC, Zouari S, Vareschi A, Elia R, Vedovi E, Scumà C, Carlucci M, Bhandary L, Mottes M, Romanelli MG, Valenti MT. Modulation of miR-146b Expression during Aging and the Impact of Physical Activity on Its Expression and Chondrogenic Progenitors. Int J Mol Sci 2023; 24:13163. [PMID: 37685971 PMCID: PMC10488278 DOI: 10.3390/ijms241713163] [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: 08/03/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
The finding of molecules associated with aging is important for the prevention of chronic degenerative diseases and for longevity strategies. MicroRNAs (miRNAs) are post-transcriptional regulators involved in many biological processes and miR-146b-5p has been shown to be involved in different degenerative diseases. However, miR-146b-5p modulation has not been evaluated in mesenchymal stem cells (MSCs) commitment or during aging. Therefore, the modulation of miR-146b-5p in the commitment and differentiation of mesenchymal cells as well as during maturation and aging in zebrafish model were analyzed. In addition, circulating miR-146b-5p was evaluated in human subjects at different age ranges. Thus, the role of physical activity in the modulation of miR-146b-5p was also investigated. To achieve these aims, RT (real-time)-PCR, Western blot, cell transfections, and three-dimensional (3D) culture techniques were applied. Our findings show that miR-146b-5p expression drives MSCs to adipogenic differentiation and increases during zebrafish maturation and aging. In addition, miR-146b-5p expression is higher in females compared to males and it is associated with the aging in humans. Interestingly, we also observed that the physical activity of walking downregulates circulating miR-146b-5p levels in human females and increases the number of chondroprogenitors. In conclusion, miR-146b-5p can be considered an age-related marker and can represent a useful marker for identifying strategies, such as physical activity, aimed at counteracting the degenerative processes of aging.
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Affiliation(s)
- Luca Dalle Carbonare
- Department of Engineering for Innovative Medicine, University of Verona, 37100 Verona, Italy; (L.D.C.); (A.M.); (M.B.); (S.Z.); (A.V.); (R.E.)
| | - Arianna Minoia
- Department of Engineering for Innovative Medicine, University of Verona, 37100 Verona, Italy; (L.D.C.); (A.M.); (M.B.); (S.Z.); (A.V.); (R.E.)
| | - Michele Braggio
- Department of Engineering for Innovative Medicine, University of Verona, 37100 Verona, Italy; (L.D.C.); (A.M.); (M.B.); (S.Z.); (A.V.); (R.E.)
| | - Jessica Bertacco
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100 Verona, Italy; (J.B.); (F.C.P.); (M.M.); (M.G.R.)
| | - Francesca Cristiana Piritore
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100 Verona, Italy; (J.B.); (F.C.P.); (M.M.); (M.G.R.)
| | - Sharazed Zouari
- Department of Engineering for Innovative Medicine, University of Verona, 37100 Verona, Italy; (L.D.C.); (A.M.); (M.B.); (S.Z.); (A.V.); (R.E.)
| | - Anna Vareschi
- Department of Engineering for Innovative Medicine, University of Verona, 37100 Verona, Italy; (L.D.C.); (A.M.); (M.B.); (S.Z.); (A.V.); (R.E.)
| | - Rossella Elia
- Department of Engineering for Innovative Medicine, University of Verona, 37100 Verona, Italy; (L.D.C.); (A.M.); (M.B.); (S.Z.); (A.V.); (R.E.)
| | - Ermes Vedovi
- Recovery and Functional Rehabilitation, Integrated University Hospital of Verona, 37100 Verona, Italy; (E.V.); (C.S.)
| | - Cristina Scumà
- Recovery and Functional Rehabilitation, Integrated University Hospital of Verona, 37100 Verona, Italy; (E.V.); (C.S.)
| | - Matilde Carlucci
- Health Directorate, Integrated University Hospital of Verona, 37100 Verona, Italy;
| | | | - Monica Mottes
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100 Verona, Italy; (J.B.); (F.C.P.); (M.M.); (M.G.R.)
| | - Maria Grazia Romanelli
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100 Verona, Italy; (J.B.); (F.C.P.); (M.M.); (M.G.R.)
| | - Maria Teresa Valenti
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100 Verona, Italy; (J.B.); (F.C.P.); (M.M.); (M.G.R.)
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Yang K, Ni M, Xu C, Wang L, Han L, Lv S, Wu W, Zheng D. Microfluidic one-step synthesis of a metal-organic framework for osteoarthritis therapeutic microRNAs delivery. Front Bioeng Biotechnol 2023; 11:1239364. [PMID: 37576986 PMCID: PMC10415039 DOI: 10.3389/fbioe.2023.1239364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023] Open
Abstract
As a class of short non-coding ribonucleic acids (RNAs), microRNAs (miRNA) regulate gene expression in human cells and are expected to be nucleic acid drugs to regulate and treat a variety of biological processes and diseases. However, the issues with potential materials toxicity, quantity production, poor cellular uptake, and endosomal entrapment limit their further applications in clinical practice. Herein, ZIF-8, a metal-organic framework with noncytotoxic zinc (II) as the metal coordination center, was selected as miRNA delivery vector was used to prepare miR-200c-3p@ZIF-8 in one step by Y-shape microfluidic chip to achieve intracellular release with low toxicity, batch size, and efficient cellular uptake. The obtained miR-200c-3p@ZIF-8 was identified by TEM, particle size analysis, XRD, XPS, and zeta potential. Compared with the traditional hydrothermal method, the encapsulation efficiency of miR-200c-3p@ZIF-8 prepared by the microfluidic method is higher, and the particle size is more uniform and controllable. The experimental results in cellular level verified that the ZIF-8 vectors with low cytotoxicity and high miRNAs loading efficiency could significantly improve cellular uptake and endosomal escape of miRNAs, providing a robust and general strategy for nucleic acid drug delivery. As a model, the prepared miR-200c-3p@ZIF-8 is confirmed to be effective in osteoarthritis treatment.
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Affiliation(s)
- Kaiyuan Yang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Min Ni
- School of Pharmacy, Changzhou University, Changzhou, China
| | - Chao Xu
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Liangliang Wang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Long Han
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Songwei Lv
- School of Pharmacy, Changzhou University, Changzhou, China
| | - Wenbo Wu
- Department of Chemistry, Institute of Molecular Aggregation Science, Tianjin University, Tianjin, China
| | - Dong Zheng
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, China
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Huang J, Li Y, Zhu S, Wang L, Pei H, Wang X, Bao T, Jiang Z, Yang L, He C. Pulsed Electromagnetic Field Promotes Bone Anabolism in Postmenopausal Osteoporosis through the miR-6976/BMP/Smad4 Axis. J Tissue Eng Regen Med 2023; 2023:8857436. [PMID: 40226399 PMCID: PMC11919207 DOI: 10.1155/2023/8857436] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 03/21/2023] [Accepted: 05/09/2023] [Indexed: 04/15/2025]
Abstract
Background Insufficient bone formation is the key reason for the imbalance of bone metabolism and one of the main mechanisms for the occurrence and deterioration of postmenopausal osteoporosis (PMOP). Accumulating evidence has demonstrated that pulsed electromagnetic field (PEMF), as a physiotherapy, can treat osteoporosis by promoting osteogenic differentiation in osteoblasts. However, little is known about its mechanisms. Methods In vivo, ovariectomized mice were administered PEMF for 4 weeks, and skeletal analysis was conducted. In vitro, hydrogen peroxide-treated mouse osteoblast precursor cells with or without PEMF intervention were subjected to osteogenic differentiation testing and miRNA microarrays. The potential target miRNAs were validated, followed by gene expression assays to further clarify their regulatory relationships with target pathways. Results We found that PEMF reduced bone loss in ovariectomized mice and promoted osteogenic differentiation of hydrogen peroxide-treated osteoblast precursor cells via downregulation of miR-6976-5p. Mechanistically, reduced miR-6976-5p enhanced the nuclear transport of phosphorylated Smad1/5/9 by upregulating Smad4, thereby activating the BMP/Smad pathway. Additionally, the administration of miR-6976-5p inhibitors successfully promoted osteogenic differentiation in vitro, and its antagomirs protected bone mass in vivo. miR-6976-5p mimics and agomirs acted in the opposite way. Conclusion These results provide evidence that PEMF alleviates estrogen deficiency-induced bone loss by activating osteoblastic progenitor cells and maintaining their osteogenic differentiation and shed light on the mechanisms involved, which may provide a potential option for the clinical application of PEMF in PMOP.
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Affiliation(s)
- Jinming Huang
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yi Li
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Siyi Zhu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Liqiong Wang
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hongliang Pei
- Human Engineering Laboratory, The School of Mechanical Engineering, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiangxiu Wang
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Tianjie Bao
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhiyuan Jiang
- Department of Plastic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Lin Yang
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chengqi He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Lai S, Deng L, Liu C, Li X, Fan L, Zhu Y, Yang Y, Mu Y. Bone marrow mesenchymal stem cell-derived exosomes loaded with miR-26a through the novel immunomodulatory peptide DP7-C can promote osteogenesis. Biotechnol Lett 2023:10.1007/s10529-023-03376-w. [PMID: 37195490 DOI: 10.1007/s10529-023-03376-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 03/28/2023] [Accepted: 04/03/2023] [Indexed: 05/18/2023]
Abstract
PURPOSE As small bioactive molecules, exosomes can deliver osteogenesis-related miRNAs to target cells and promote osteogenesis. This study aimed to investigate miR-26a as a therapeutic cargo to be loaded into bone marrow stromal cell exosomes through a novel immunomodulatory peptide (DP7-C). METHODS After transfecting BMSCs with DP7-C as a transfection agent, exosomes were extracted by ultracentrifugation from the culture supernatant of miR-26a-modified BMSCs. We then characterized and identified the engineered exosomes. The effect of the engineered exosomes on osteogenesis was then evaluated in vitro and in vivo, including transwell, wound healing, modified alizarin red staining, western blot, real-time quantitative PCR, and experimental periodontitis assays. Bioinformatics and data analyses were conducted to investigate the role of miR-26a in bone regeneration. RESULTS The DP7-C/miR-26a complex successfully transfected miR-26a into BMSCs and stimulated them to release more than 300 times the amount of exosomes overexpressing miR-26a compared with the ExoNC group. Furthermore, exosomes loaded with miR-26a could enhance proliferation, migration, and osteogenic differentiation of BMSCs in vitro compared with the ExoNC and blank groups. In vivo, the ExomiR-26a group inhibited the destruction of periodontitis compared with the ExoNC and blank groups, as revealed by HE staining. Micro-CT indicated that treatment of ExomiR-26a increased the percent bone volume and the bone mineral density compared with those of the ExoNC (P < 0.05) and blank groups (P < 0.001). Target gene analysis indicated that the osteogenic effect of miR-26a is related to the mTOR pathway. CONCLUSION miR-26a can be encapsulated into exosomes through DP7-C. Exosomes loaded with miR-26a can promote osteogenesis and inhibit bone loss in experimental periodontitis and serve as the foundation for a novel treatment strategy.
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Affiliation(s)
- Shuang Lai
- Department of Stomatology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic and Technology of China, Chengdu, 611731, Sichuan, China
| | - Li Deng
- Department of Stomatology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic and Technology of China, Chengdu, 611731, Sichuan, China
| | - Cong Liu
- Department of Stomatology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic and Technology of China, Chengdu, 611731, Sichuan, China
| | - Xinlun Li
- Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Liyuan Fan
- Department of Stomatology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic and Technology of China, Chengdu, 611731, Sichuan, China
| | - Yushu Zhu
- Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yiling Yang
- Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yandong Mu
- Department of Stomatology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic and Technology of China, Chengdu, 611731, Sichuan, China.
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Loh HY, Norman BP, Lai KS, Cheng WH, Nik Abd Rahman NMA, Mohamed Alitheen NB, Osman MA. Post-Transcriptional Regulatory Crosstalk between MicroRNAs and Canonical TGF-β/BMP Signalling Cascades on Osteoblast Lineage: A Comprehensive Review. Int J Mol Sci 2023; 24:ijms24076423. [PMID: 37047394 PMCID: PMC10094338 DOI: 10.3390/ijms24076423] [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: 11/07/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 04/14/2023] Open
Abstract
MicroRNAs (miRNAs) are a family of small, single-stranded, and non-protein coding RNAs about 19 to 22 nucleotides in length, that have been reported to have important roles in the control of bone development. MiRNAs have a strong influence on osteoblast differentiation through stages of lineage commitment and maturation, as well as via controlling the activities of osteogenic signal transduction pathways. Generally, miRNAs may modulate cell stemness, proliferation, differentiation, and apoptosis by binding the 3'-untranslated regions (3'-UTRs) of the target genes, which then can subsequently undergo messenger RNA (mRNA) degradation or protein translational repression. MiRNAs manage the gene expression in osteogenic differentiation by regulating multiple signalling cascades and essential transcription factors, including the transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP), Wingless/Int-1(Wnt)/β-catenin, Notch, and Hedgehog signalling pathways; the Runt-related transcription factor 2 (RUNX2); and osterix (Osx). This shows that miRNAs are essential in regulating diverse osteoblast cell functions. TGF-βs and BMPs transduce signals and exert diverse functions in osteoblastogenesis, skeletal development and bone formation, bone homeostasis, and diseases. Herein, we highlighted the current state of in vitro and in vivo research describing miRNA regulation on the canonical TGF-β/BMP signalling, their effects on osteoblast linage, and understand their mechanism of action for the development of possible therapeutics. In this review, particular attention and comprehensive database searches are focused on related works published between the years 2000 to 2022, using the resources from PubMed, Google Scholar, Scopus, and Web of Science.
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Affiliation(s)
- Hui-Yi Loh
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Brendan P Norman
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK
| | - Kok-Song Lai
- Health Sciences Division, Abu Dhabi Women's College, Higher Colleges of Technology, Abu Dhabi 41012, United Arab Emirates
| | - Wan-Hee Cheng
- Faculty of Health and Life Sciences, INTI International University, Persiaran Perdana BBN, Putra Nilai, Nilai 71800, Negeri Sembilan, Malaysia
| | - Nik Mohd Afizan Nik Abd Rahman
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Noorjahan Banu Mohamed Alitheen
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Mohd Azuraidi Osman
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
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Delivery of microRNA-302a-3p by APTES modified hydroxyapatite nanoparticles to promote osteogenic differentiation in vitro. BDJ Open 2023; 9:8. [PMID: 36813762 PMCID: PMC9947005 DOI: 10.1038/s41405-023-00135-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/26/2023] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
OBJECTIVE To demonstrate the miRNA delivery by hydroxyapatite nanoparticles modified with APTES (HA-NPs-APTES) and promote osteogenic gene expression. MATERIALS AND METHODS Osteosarcoma cells (HOS, MG-63) and primary human mandibular osteoblasts (HmOBs) were co-cultured with HA-NPs-APTES conjugated with miRNA-302a-3p. Resazurin reduction assay was performed to evaluate HA-NPs-APTES biocompatibility. Intracellular uptake was demonstrated by confocal fluorescent and scanning electron microscopy. The miRNA-302a-3p and its mRNA targets expression levels including COUP-TFII and other osteogenic genes were assessed by qPCR on day1 or day5 post-delivery. Calcium deposition induced by the osteogenic gene upregulation was shown by alizarin red staining on day7 and 14 post-delivery. RESULTS Proliferation of HOS cells treated with HA-NPs-APTES was similar to that of untreated cells. HA-NPs-APTES was visualized in cell cytoplasm within 24 hours. MiRNA-302a-3p level was upregulated in HOS, MG-63 and HmOBs as compared to untreated cells. As a result, COUP-TFII mRNA expression was reduced, followed by an increase of RUNX2 and other osteogenic genes mRNA expression. Calcium deposition induced by HA-NPs-APTES-miR-302a-3p in HmOBs was significantly higher than in untreated cells. CONCLUSION HA-NPs-APTES may support the delivery of miRNA-302a-3p into bone cells, as assessed by osteogenic gene expression and differentiation improvement once this combination is used on osteoblast cultures.
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Long Z, Dou P, Cai W, Mao M, Wu R. MiR-181a-5p promotes osteogenesis by targeting BMP3. Aging (Albany NY) 2023; 15:734-747. [PMID: 36734882 PMCID: PMC9970307 DOI: 10.18632/aging.204505] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/18/2023] [Indexed: 02/04/2023]
Abstract
High-throughput microRNA (miRNA) sequencing of osteoporosis was analyzed from the Gene Expression Omnibus (GEO) database to investigate specific microRNAs that control osteogenesis. MiR-181a-5p was differentially expressed among healthy subjects and those with osteoporosis. Inhibitors and mimics were transfected into cells to modulate miR-181a-5p levels to examine the role in MC3T3-E1 functions. Alkaline phosphatase (ALP) staining and Alizarin Red S (ARS) staining were used for morphological detection, and proteins of ALP and Runt-related transcription factor 2 (RUNX2), as osteogenesis markers, were detected. During the osteogenic differentiation of MC3T3-E1, the transcription level of miR-181a-5p was significantly increased. The inhibition of miR-181a-5p suppressed MC3T3-E1 osteogenic differentiation, whereas its overexpression functioned oppositely. Consistently, the miR-181a-5p antagomir aggravated osteoporosis in old mice. Additionally, we predicted potential target genes via TargetScan and miRDB and identified bone morphogenetic protein 3 (BMP3) as the target gene. Moreover, the reduced expression of miR-181a-5p was validated in our hospitalized osteoporotic patients. These findings have substantial implications for the strategies targeting miR-181a-5p to prevent osteoporosis and potential related fractures.
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Affiliation(s)
- Ze Long
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Pengcheng Dou
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Weiliang Cai
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Minzhi Mao
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ren Wu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
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Liu J, Chang X, Dong D. MicroRNA-181a-5p Curbs Osteogenic Differentiation and Bone Formation Partially Through Impairing Runx1-Dependent Inhibition of AIF-1 Transcription. Endocrinol Metab (Seoul) 2023; 38:156-173. [PMID: 36604945 PMCID: PMC10008668 DOI: 10.3803/enm.2022.1516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/01/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGRUOUND Evidence has revealed the involvement of microRNAs (miRNAs) in modulating osteogenic differentiation, implying the promise of miRNA-based therapies for treating osteoporosis. This study investigated whether miR-181a-5p influences osteogenic differentiation and bone formation and aimed to establish the mechanisms in depth. METHODS Clinical serum samples were obtained from osteoporosis patients, and MC3T3-E1 cells were treated with osteogenic induction medium (OIM) to induce osteogenic differentiation. miR-181a-5p-, Runt-related transcription factor 1 (Runx1)-, and/or allograft inflammatory factor-1 (AIF-1)-associated oligonucleotides or vectors were transfected into MC3T3-E1 cells to explore their function in relation to the number of calcified nodules, alkaline phosphatase (ALP) staining and activity, expression levels of osteogenesis-related proteins, and apoptosis. Luciferase activity, RNA immunoprecipitation, and chromatin immunoprecipitation assays were employed to validate the binding relationship between miR-181a-5p and Runx1, and the transcriptional regulatory relationship between Runx1 and AIF-1. Ovariectomy (OVX)-induced mice were injected with a miR-181a-5p antagonist for in vivo verification. RESULTS miR-181a-5p was highly expressed in the serum of osteoporosis patients. OIM treatment decreased miR-181a-5p and AIF-1 expression, but promoted Runx1 expression in MC3T-E1 cells. Meanwhile, upregulated miR-181a-5p suppressed OIM-induced increases in calcified nodules, ALP content, and osteogenesis-related protein expression. Mechanically, miR-181a-5p targeted Runx1, which acted as a transcription factor to negatively modulate AIF-1 expression. Downregulated Runx1 suppressed the miR-181a-5p inhibitor-mediated promotion of osteogenic differentiation, and downregulated AIF-1 reversed the miR-181a-5p mimic-induced inhibition of osteogenic differentiation. Tail vein injection of a miR-181a-5p antagonist induced bone formation in OVX-induced osteoporotic mice. CONCLUSION In conclusion, miR-181a-5p affects osteogenic differentiation and bone formation partially via the modulation of the Runx1/AIF-1 axis.
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Affiliation(s)
- Jingwei Liu
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xueying Chang
- Department of Nephrology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Daming Dong
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Corresponding author: Daming Dong. Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Road, Nangang District, Harbin, Heilongjiang 150001, China Tel: +86-0451-53643856, Fax: +86-0451-53643856, E-mail:
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lncRNA MEG3 Promotes PDK4/GSK-3 β/ β-Catenin Axis in MEFs by Targeting miR-532-5p. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:3563663. [PMID: 36778210 PMCID: PMC9908332 DOI: 10.1155/2023/3563663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 05/16/2022] [Accepted: 09/26/2022] [Indexed: 02/04/2023]
Abstract
Studies reported the positive and negative osteogenic effects of MEG3 in mesenchymal stem cells (MSCs). This study aims at clarifying the osteogenic potential of MEG3 and the underlying mechanism. Bone morphogenetic protein 9- (BMP9-) transfected MSCs were recruited as an osteogenic model in vitro, and ectopic bone formation were used in vivo to explore the effect of MEG3 on osteogenesis. We found that overexpression of MEG3 facilitated BMP9-induced osteogenic markers, ALP activities, and matrix mineralization. However, knockdown of MEG3 attenuated BMP9-induced osteogenic markers. MEG3 increased the phosphorylation of GSK-3β and the protein level of β-catenin. Pyruvate dehydrogenase kinase 4 (PDK4) can also combine with GSK-3β and increase the latter phosphorylation. Moreover, MEG3 increased the mRNA level of PDK4. The ceRNA analysis showed that MEG3 may regulate the expression of PDK4 via microRNA 532-5p (miR-532-5p). The MEG3-enhanced GSK-3β/β-catenin axis can be attenuated by miR-532-5p, and miR-532-5p inhibitor partly rescued endogenous PDK4 and MEG3-mediated expression of PDK4. MEG3 may potentiate PDK4 and GSK-3β/β-catenin by inhibiting miR-532-5p.
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Wang T, Zhao H, Jing S, Fan Y, Sheng G, Ding Q, Liu C, Wu H, Liu Y. Magnetofection of miR-21 promoted by electromagnetic field and iron oxide nanoparticles via the p38 MAPK pathway contributes to osteogenesis and angiogenesis for intervertebral fusion. J Nanobiotechnology 2023; 21:27. [PMID: 36694219 PMCID: PMC9875474 DOI: 10.1186/s12951-023-01789-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Magnetofection-mediated gene delivery shows great therapeutic potential through the regulation of the direction and degree of differentiation. Lumbar degenerative disc disease (DDD) is a serious global orthopaedic problem. However, even though intervertebral fusion is the gold standard for the treatment of DDD, its therapeutic effect is unsatisfactory. Here, we described a novel magnetofection system for delivering therapeutic miRNAs to promote osteogenesis and angiogenesis in patients with lumbar DDD. RESULTS Co-stimulation with electromagnetic field (EMF) and iron oxide nanoparticles (IONPs) enhanced magnetofection efficiency significantly. Moreover, in vitro, magnetofection of miR-21 into bone marrow mesenchymal stem cells (BMSCs) and human umbilical endothelial cells (HUVECs) influenced their cellular behaviour and promoted osteogenesis and angiogenesis. Then, gene-edited seed cells were planted onto polycaprolactone (PCL) and hydroxyapatite (HA) scaffolds (PCL/HA scaffolds) and evolved into the ideal tissue-engineered bone to promote intervertebral fusion. Finally, our results showed that EMF and polyethyleneimine (PEI)@IONPs were enhancing transfection efficiency by activating the p38 MAPK pathway. CONCLUSION Our findings illustrate that a magnetofection system for delivering miR-21 into BMSCs and HUVECs promoted osteogenesis and angiogenesis in vitro and in vivo and that magnetofection transfection efficiency improved significantly under the co-stimulation of EMF and IONPs. Moreover, it relied on the activation of p38 MAPK pathway. This magnetofection system could be a promising therapeutic approach for various orthopaedic diseases.
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Affiliation(s)
- Tianqi Wang
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Hongqi Zhao
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Shaoze Jing
- grid.470966.aThird Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032 China
| | - Yang Fan
- grid.412793.a0000 0004 1799 5032Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Gaohong Sheng
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qing Ding
- grid.412793.a0000 0004 1799 5032Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Chaoxu Liu
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Hua Wu
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yang Liu
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
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48
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Peng X, Wang Q, Li W, Ge G, Peng J, Xu Y, Yang H, Bai J, Geng D. Comprehensive overview of microRNA function in rheumatoid arthritis. Bone Res 2023; 11:8. [PMID: 36690624 PMCID: PMC9870909 DOI: 10.1038/s41413-023-00244-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 11/15/2022] [Accepted: 12/04/2022] [Indexed: 01/25/2023] Open
Abstract
MicroRNAs (miRNAs), a class of endogenous single-stranded short noncoding RNAs, have emerged as vital epigenetic regulators of both pathological and physiological processes in animals. They direct fundamental cellular pathways and processes by fine-tuning the expression of multiple genes at the posttranscriptional level. Growing evidence suggests that miRNAs are implicated in the onset and development of rheumatoid arthritis (RA). RA is a chronic inflammatory disease that mainly affects synovial joints. This common autoimmune disorder is characterized by a complex and multifaceted pathogenesis, and its morbidity, disability and mortality rates remain consistently high. More in-depth insights into the underlying mechanisms of RA are required to address unmet clinical needs and optimize treatment. Herein, we comprehensively review the deregulated miRNAs and impaired cellular functions in RA to shed light on several aspects of RA pathogenesis, with a focus on excessive inflammation, synovial hyperplasia and progressive joint damage. This review also provides promising targets for innovative therapies of RA. In addition, we discuss the regulatory roles and clinical potential of extracellular miRNAs in RA, highlighting their prospective applications as diagnostic and predictive biomarkers.
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Affiliation(s)
- Xiaole Peng
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
| | - Qing Wang
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
| | - Wenming Li
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
| | - Gaoran Ge
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
| | - Jiachen Peng
- grid.413390.c0000 0004 1757 6938Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, 563000 Zunyi, P. R. China
| | - Yaozeng Xu
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
| | - Huilin Yang
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
| | - Jiaxiang Bai
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
| | - Dechun Geng
- grid.429222.d0000 0004 1798 0228Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006 Jiangsu P. R. China
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Sun J, Ru J, Ramos-Mucci L, Qi F, Chen Z, Chen S, Cribbs AP, Deng L, Wang X. DeepsmirUD: Prediction of Regulatory Effects on microRNA Expression Mediated by Small Molecules Using Deep Learning. Int J Mol Sci 2023; 24:1878. [PMID: 36768205 PMCID: PMC9915273 DOI: 10.3390/ijms24031878] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/26/2022] [Accepted: 01/12/2023] [Indexed: 01/21/2023] Open
Abstract
Aberrant miRNA expression has been associated with a large number of human diseases. Therefore, targeting miRNAs to regulate their expression levels has become an important therapy against diseases that stem from the dysfunction of pathways regulated by miRNAs. In recent years, small molecules have demonstrated enormous potential as drugs to regulate miRNA expression (i.e., SM-miR). A clear understanding of the mechanism of action of small molecules on the upregulation and downregulation of miRNA expression allows precise diagnosis and treatment of oncogenic pathways. However, outside of a slow and costly process of experimental determination, computational strategies to assist this on an ad hoc basis have yet to be formulated. In this work, we developed, to the best of our knowledge, the first cross-platform prediction tool, DeepsmirUD, to infer small-molecule-mediated regulatory effects on miRNA expression (i.e., upregulation or downregulation). This method is powered by 12 cutting-edge deep-learning frameworks and achieved AUC values of 0.843/0.984 and AUCPR values of 0.866/0.992 on two independent test datasets. With a complementarily constructed network inference approach based on similarity, we report a significantly improved accuracy of 0.813 in determining the regulatory effects of nearly 650 associated SM-miR relations, each formed with either novel small molecule or novel miRNA. By further integrating miRNA-cancer relationships, we established a database of potential pharmaceutical drugs from 1343 small molecules for 107 cancer diseases to understand the drug mechanisms of action and offer novel insight into drug repositioning. Furthermore, we have employed DeepsmirUD to predict the regulatory effects of a large number of high-confidence associated SM-miR relations. Taken together, our method shows promise to accelerate the development of potential miRNA targets and small molecule drugs.
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Affiliation(s)
- Jianfeng Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
- Botnar Research Centre, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Jinlong Ru
- Institute of Virology, Helmholtz Centre Munich—German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Chair of Prevention of Microbial Diseases, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany
| | - Lorenzo Ramos-Mucci
- Botnar Research Centre, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Fei Qi
- Institute of Genomics, School of Medicine, Huaqiao University, Xiamen 362021, China
| | - Zihao Chen
- Department of Computational Biology for Drug Discovery, Biolife Biotechnology Ltd., Zhumadian 463200, China
| | - Suyuan Chen
- Leibniz-Institut für Analytische Wissenschaften–ISAS–e.V., Otto-Hahn-Str asse 6b, 44227 Dortmund, Germany
| | - Adam P. Cribbs
- Botnar Research Centre, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Li Deng
- Institute of Virology, Helmholtz Centre Munich—German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Chair of Prevention of Microbial Diseases, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany
| | - Xia Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA
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50
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Cao Y, Jing P, Yu L, Wu Z, Gao S, Bao W. miR-214-5p/C1QTNF1 axis enhances PCV2 replication through promoting autophagy by targeting AKT/mTOR signaling pathway. Virus Res 2023; 323:198990. [PMID: 36302471 PMCID: PMC10194317 DOI: 10.1016/j.virusres.2022.198990] [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: 07/31/2022] [Revised: 10/18/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022]
Abstract
Porcine circovirus type 2 (PCV2) is the causative agent of PCV2-associated disease, which causes a relevant economic impact on the global swine industry. Accumulating data have indicated host microRNAs play essential roles in numerous virus replication of pigs, while their roles in PCV2 replication remain unclear. Herein, we demonstrated that PCV2 infection downregulated the expression of miR-214-5p in PK15 cells, and miR-214-5p promoted PCV2 replication. C1q/tumor necrosis factor-related protein 1 (C1QTNF1) was then identified as a target gene of miR-214-5p, and C1QTNF1 suppressed PCV2 replication. Interestingly, miR-214-5p/C1QTNF1 axis negatively regulated AKT/mTOR signaling, and then enhanced PCV2 replication through promoting autophagy in PK15 cells. Collectively, our findings provide insight into the mechanism of PCV2 replication and highlight miR-214-5p and C1QTNF1 as potential novel targets for the treatment of PCV2 infection.
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Affiliation(s)
- Yue Cao
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Pengfei Jing
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Luchen Yu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Zhengchang Wu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China; College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.
| | - Song Gao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.
| | - Wenbin Bao
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
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