|
1
|
Kwok CTK, Wong CC, Li JJ, Kwan YW, Leung GPH, Tsoi B, Chow FWN, Seto SW. Lipopolysaccharide (LPS) induces sclerostin secretion by extracellular vesicle via TLR4/miR-92a-3p/PTEN/NF-κB signalling pathway in murine macrophage. Inflamm Res 2025; 74:27. [PMID: 39862242 DOI: 10.1007/s00011-024-01987-1] [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: 06/11/2024] [Revised: 09/28/2024] [Accepted: 10/14/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Sclerostin (SOST) is traditionally regarded as an osteocyte-derived secreted glycoprotein that regulates bone mineralization. Recent studies reported that SOST is also released from non-skeletal sources, especially during inflammation. However, the cellular source and regulatory mechanisms governing SOST generation in inflammation remain unclear. This study investigated whether macrophages produce SOST in response to inflammatory stimuli and determined associated regulatory pathways. METHODS The effect of lipopolysaccharide (LPS)-induced inflammation in SOST generation and its underlying regulatory mechanism was examined on mouse macrophage RAW 264.7 by western blot and immunofluorescent staining. Transfection with miR-92a-3p mimic and inhibitor were used to validate its role in SOST production. The role of NF-κB and TLR4 were studied using pharmacological inhibitors BAY 11-7085 and TAK242, respectively. The involvement of NF-κB and TLR4 in LPS-induced SOST production was further validated through nuclear NF-κB p65 immunoprecipitation and TLR4 small interfering RNA (siRNA) experiments, respectively.GW4869 and manumycin A (extracellular vesicles (EV) biogenesis inhibitors) were used to examine the associated of SOST and EV. Finally, SOST expression and characteristics of the isolated EV were assessed by Western blot and nanoparticle tracking analysis (NTA). RESULTS LPS significantly induced SOST protein expression and secretion in RAW 264.7. MiR-92a-3p was upregulated by LPS stimulation in macrophages. Transfection of miR-92a-3p mimic increased SOST generation in RAW 264.7. Inhibition of TLR4 and NF-κB signalling pathways using pharmacological inhibitors significantly suppressed LPS-induced SOST in RAW 264.7. Similarly, TLR4 siRNA effectively suppressed LPS-induced SOST level. However, the LPS-induced upregulation of miR-92a-3p was only regulated by TLR4, but not by NF-κB. NF-κB was found to directly bind to the mouse sost promoter, thereby activating sost transcription. Additionally, SOST secretion was found predominantly associated with EV from LPS-stimulated cells, and inhibition of EV biogenesis suppressed SOST production in RAW 264.7 cells. CONCLUSIONS In conclusion, our study showed, for the first time, that LPS induced SOST generation and secretion via TLR4/miR-92a-3p/PTEN/NF-κB singling pathway in murine macrophage RAW 264.7 cells. Moreover, we showed that SOST is secreted from the RAW 264.7 cells in the form of extracellular vesicle. This study identified macrophage as a novel source of SOST, highlighting its potential role in inflammatory diseases.
Collapse
Affiliation(s)
- Carsten Tsun-Ka Kwok
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, SAR, China
| | - Chun-Chak Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, China
| | - Jing-Jing Li
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, SAR, China
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Yiu-Wa Kwan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - George Pak-Heng Leung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, SAR, China
| | - Bun Tsoi
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, SAR, China
- Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong, SAR, China
| | - Franklin Wang-Ngai Chow
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, SAR, China.
| | - Sai-Wang Seto
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, SAR, China.
- Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong, SAR, China.
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, 2751, Australia.
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.
| |
Collapse
|
|
2
|
Qian JK, Ma Y, Huang X, Li XR, Xu YF, Liu ZY, Gu Y, Shen K, Tian LJ, Wang YT, Cheng NN, Yang BS, Huang KY, Chai Y, Liu GQ, Cui NQ, Deng SY, Jiang N, Xu DR, Yu B. The CD163/TWEAK/Fn14 axis: A potential therapeutic target for alleviating inflammatory bone loss. J Orthop Translat 2024; 49:82-95. [PMID: 39430128 PMCID: PMC11488420 DOI: 10.1016/j.jot.2024.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 08/21/2024] [Accepted: 09/01/2024] [Indexed: 10/22/2024] Open
Abstract
Objective Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.
Collapse
Affiliation(s)
- Ji-kun Qian
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, The Seventh Affiliated Hospital, Southern Medical University, Foshan, 528200, China
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yuan Ma
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xuan Huang
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiao-ran Li
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ya-fei Xu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, The Seventh Affiliated Hospital, Southern Medical University, Foshan, 528200, China
| | - Zi-ying Liu
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yuan Gu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ke Shen
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Liang-jie Tian
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yu-tian Wang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ning-ning Cheng
- Department of Obstetrics, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Bing-sheng Yang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kui-yuan Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330000, China
| | - Yu Chai
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Guan-qiao Liu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Nai-qian Cui
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Song-yun Deng
- Department of Orthopaedics and Traumatology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Nan Jiang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Dao-rong Xu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Bin Yu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| |
Collapse
|
|
3
|
Sim N, Carter JM, Deka K, Tan BKT, Sim Y, Tan SM, Li Y. TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer. Nat Commun 2024; 15:5638. [PMID: 38965263 PMCID: PMC11224303 DOI: 10.1038/s41467-024-50071-z] [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: 07/28/2023] [Accepted: 06/27/2024] [Indexed: 07/06/2024] Open
Abstract
Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from limited targeted treatment options. Following recent reports correlating Fibroblast growth factor-inducible 14 (Fn14) receptor overexpression in Estrogen Receptor (ER)-negative breast cancers with metastatic events, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of Nicotinamide phosphoribosyltransferase (NAMPT), which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients.
Collapse
Affiliation(s)
- Nicholas Sim
- School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore
| | - Jean-Michel Carter
- School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore
| | - Kamalakshi Deka
- School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore
| | - Benita Kiat Tee Tan
- Division of Surgery and Surgical Oncology, Department of Breast Surgery, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Singapore
- Division of Surgery and Surgical Oncology, Department of Breast Surgery, Singapore General Hospital, 31 Third Hospital Ave, Singapore, 168753, Singapore
- SingHealth Duke-NUS Breast Centre, Singapore, Singapore
| | - Yirong Sim
- Division of Surgery and Surgical Oncology, Department of Breast Surgery, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Singapore
- Division of Surgery and Surgical Oncology, Department of Breast Surgery, Singapore General Hospital, 31 Third Hospital Ave, Singapore, 168753, Singapore
- SingHealth Duke-NUS Breast Centre, Singapore, Singapore
| | - Suet-Mien Tan
- School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore
| | - Yinghui Li
- School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore.
| |
Collapse
|
|
4
|
Szeremeta A, Jura-Półtorak A, Zoń-Giebel A, Olczyk K, Komosińska-Vassev K. Plasma Sclerostin Levels in Rheumatoid Arthritis Women on TNF-α Inhibitor Therapy. Pharmaceuticals (Basel) 2024; 17:666. [PMID: 38931334 PMCID: PMC11206420 DOI: 10.3390/ph17060666] [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: 04/10/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Rheumatoid arthritis (RA) is associated with significant systemic and local bone loss. The aim of this study was to assess whether or not 15-month tumor necrosis factor α inhibitor (TNFαI) therapy in combination with methotrexate (MTX) affects circulating levels of sclerostin (SOST) in female RA patients. Plasma levels of SOST were measured using immunoassays kits. Baseline SOST levels showed no significant differences between RA patients and control participants. Postmenopausal women with RA tended to have higher sclerostin levels than premenopausal woman with RA. After 15 months of treatment with TNFαI, plasma levels of SOST were decreased. Before starting biological therapy, circulating levels of SOST significantly correlated with the patient's age (p < 0.05) and the marker of inflammation, such as ESR (p < 0.05). Multivariate regression analysis showed that age was the only significant predictor for baseline SOST levels in women with RA (β = 0.008, p = 0.028, R2 model = 0.293). Moreover, a positive correlation between SOST levels and the 28 joint disease activity score value based on the erythrocyte sedimentation rate (DAS28-ESR) was found at baseline (p < 0.05), as well as after 15 months of biological therapy (p < 0.05). Thus, plasma SOST levels may be helpful for monitoring the efficacy of TNFαI treatment in RA patients. According to our results, TNFαI, in combination with MTX, has a beneficial effect on bone turnover with a significant reduction in bone metabolism marker SOST.
Collapse
Affiliation(s)
- Anna Szeremeta
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
| | - Agnieszka Jura-Półtorak
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
| | - Aleksandra Zoń-Giebel
- Department of Rheumatology and Rehabilitation, Specialty Hospital No. 1, Żeromskiego 7, 41-902 Bytom, Poland;
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
| |
Collapse
|
|
5
|
Zhao D, Wu L, Hong M, Zheng S, Wu X, Ye H, Chen F, Zhang D, Liu X, Meng X, Chen X, Chen S, Zhu J, Li J. DKK-1 and Its Influences on Bone Destruction: A Comparative Study in Collagen-Induced Arthritis Mice and Rheumatoid Arthritis Patients. Inflammation 2024; 47:129-144. [PMID: 37688661 DOI: 10.1007/s10753-023-01898-z] [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: 06/08/2023] [Revised: 08/07/2023] [Accepted: 08/26/2023] [Indexed: 09/11/2023]
Abstract
Dickkopf-1 (DKK-1) has been considered a master regulator of bone remodeling. As precursors of osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs) were previously shown to participate in the process of bone destruction in rheumatoid arthritis (RA). However, the role of DKK-1 and MDSCs in RA is not yet fully understood. We investigated the relevance between the level of DKK-1 and the expression of MDSCs in different tissues and joint destruction in RA patients and collagen-induced arthritis (CIA) mouse models. Furthermore, the CIA mice were administered recombinant DKK-1 protein. The arthritis scores, bone destruction, and the percentage of MDSCs in the peripheral blood and spleen were monitored. In vitro, the differentiation of MDSCs into OCs was intervened with recombinant protein and inhibitor of DKK-1. The number of OCs differentiated and the protein expression of the Wnt/β-catenin signaling pathway were explored. The level of DKK-1 positively correlates with the frequency of MDSCs and bone erosion in RA patients and CIA mice. Strikingly, recombinant DKK-1 intervention significantly exacerbated arthritis scores and bone destruction, increasing the percentage of MDSCs in the peripheral blood and spleen in CIA mice. In vitro experiments showed that recombinant DKK-1 promoted the differentiation of MDSCs into OCs, reducing the expression of β-catenin and TCF4 and increasing the expression of CyclinD1. In contrast, the DKK-1 inhibitor had the opposite effect. Our findings highlight that DKK-1 promoted MDSCs expansion in RA and enhanced the differentiation of MDSCs into OCs via targeting the Wnt/β-catenin pathway, aggravating the bone destruction in RA.
Collapse
Affiliation(s)
- Di Zhao
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lisheng Wu
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Mukeng Hong
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Songyuan Zheng
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xianghui Wu
- Laboratory Animal Research Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haixin Ye
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Feilong Chen
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Dingding Zhang
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xinhang Liu
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiangyun Meng
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoyun Chen
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shixian Chen
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Junqing Zhu
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Juan Li
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
6
|
Takami K, Okamoto K, Etani Y, Hirao M, Miyama A, Okamura G, Goshima A, Miura T, Kurihara T, Fukuda Y, Kanamoto T, Nakata K, Okada S, Ebina K. Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomy-induced osteoporosis in mice. JCI Insight 2023; 8:e171962. [PMID: 37991021 PMCID: PMC10721323 DOI: 10.1172/jci.insight.171962] [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: 05/03/2023] [Accepted: 10/10/2023] [Indexed: 11/23/2023] Open
Abstract
NF-κB is a transcription factor that is activated with aging. It plays a key role in the development of osteoporosis by promoting osteoclast differentiation and inhibiting osteoblast differentiation. In this study, we developed a small anti-NF-κB peptide called 6A-8R from a nuclear acidic protein (also known as macromolecular translocation inhibitor II, Zn2+-binding protein, or parathymosin) that inhibits transcriptional activity of NF-κB without altering its nuclear translocation and binding to DNA. Intraperitoneal injection of 6A-8R attenuated ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation, promoting osteoblast differentiation, and inhibiting sclerostin production by osteocytes in vivo with no apparent side effects. Conversely, in vitro, 6A-8R inhibited osteoclast differentiation by inhibiting NF-κB transcriptional activity, promoted osteoblast differentiation by promoting Smad1 phosphorylation, and inhibited sclerostin expression in osteocytes by inhibiting myocyte enhancer factors 2C and 2D. These findings suggest that 6A-8R has the potential to be an antiosteoporotic therapeutic agent with uncoupling properties.
Collapse
Affiliation(s)
- Kenji Takami
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Orthopaedic Surgery, Nippon Life Hospital, Nishi-ku, Osaka, Japan
| | - Kazuki Okamoto
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuki Etani
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Makoto Hirao
- Department of Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Osaka, Japan
| | - Akira Miyama
- Department of Orthopaedic Surgery, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan
| | - Gensuke Okamura
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, Kita-ku, Sakai, Japan
| | - Atsushi Goshima
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Taihei Miura
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takuya Kurihara
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuji Fukuda
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | | | - Ken Nakata
- Department of Health and Sport Sciences, and
| | - Seiji Okada
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kosuke Ebina
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| |
Collapse
|
|
7
|
Ozer H, Baloglu İ, Aykut T, Demirci MA, Aydemir FHY, Turkmen K. Sclerostin and TNF-related weak inducer of apoptosis: can they be important in the patients with glomerulonephritis? REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:e20230239. [PMID: 37466605 PMCID: PMC10351990 DOI: 10.1590/1806-9282.20230239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/28/2023] [Indexed: 07/20/2023]
Abstract
OBJECTIVE Sclerostin is a protein produced by osteocytes, kidneys, and vascular cells and has many effects on kidney and vascular structures. Soluble TNF-related weak inducer of apoptosis is a proinflammatory cytokine that may cause glomerular and tubular injury and increase sclerostin expression. This study aimed to investigate serum sclerostin and soluble TNF-related weak inducer of apoptosis levels in patients with glomerulonephritis and the effects they may be associated with. METHODS This cross-sectional study included 93 patients, 63 of whom were glomerulonephritis and 30 were healthy controls. Serum sclerostin, soluble TNF-related weak inducer of apoptosis, and 24-h urinary protein excretion were measured, and pulse wave velocity was calculated for arterial stiffness. RESULTS Serum sclerostin and soluble TNF-related weak inducer of apoptosis were higher in glomerulonephritis patients than in the control group, and serum sclerostin and soluble TNF-related weak inducer of apoptosis levels were correlated with both proteinuria and pulse wave velocity. In addition, in the regression analysis, serum sclerostin and soluble TNF-related weak inducer of apoptosis levels were found to be independent predictors of proteinuria in patients with glomerulonephritis. CONCLUSION This is the first study to show that serum sclerostin and soluble TNF-related weak inducer of apoptosis are elevated in glomerulonephritis patients, and these two markers correlate with arterial stiffness and proteinuria in these patients. Considering the effects of sclerostin and soluble TNF-related weak inducer of apoptosis in patients with glomerulonephritis, we think these mechanisms will be the target of both diagnosis and new therapies.
Collapse
Affiliation(s)
- Hakan Ozer
- Necmettin Erbakan University, Meram School of Medicine, Department of Nephrology - Konya, Turkey
| | - İsmail Baloglu
- Necmettin Erbakan University, Meram School of Medicine, Department of Nephrology - Konya, Turkey
| | - Talat Aykut
- Bursa Yenisehir Hospital, Specialist Internal Medicine - Bursa, Turkey
| | - Mehmet Ali Demirci
- Necmettin Erbakan University, Meram School of Medicine, Department of Internal Medicine - Konya, Turkey
| | | | - Kultigin Turkmen
- Necmettin Erbakan University, Meram School of Medicine, Department of Nephrology - Konya, Turkey
| |
Collapse
|
|
8
|
Gu JJ, Deng CC, Feng QL, Liu J, Zhu DH, Cheng Q, Rong Z, Yang B. Relief of Extracellular Matrix Deposition Repression by Downregulation of IRF1-Mediated TWEAK/Fn14 Signaling in Keloids. J Invest Dermatol 2023; 143:1208-1219.e6. [PMID: 36716919 DOI: 10.1016/j.jid.2023.01.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/04/2023] [Accepted: 01/07/2023] [Indexed: 01/29/2023]
Abstract
Keloids represent a fibrotic disorder characterized by the excessive deposition of extracellular matrix (ECM). However, the mechanisms through which ECM deposition in keloids is regulated remain elusive. In this study, we found that the expression of both TWEAK and its cognate receptor Fn14 was significantly downregulated in keloids and that TWEAK/Fn14 signaling repressed the expression of ECM-related genes in keloid fibroblasts. The IRF1 gene was essential for this repression, and the TWEAK/Fn14 downstream transcription factor p65 directly bound to the promoter of the IRF1 gene and induced its expression. Furthermore, in patients with keloid, the expression of TWEAK and Fn14 was negatively correlated with that of ECM genes and positively correlated with that of IRF1. These observations indicate that relief of TWEAK/Fn14/IRF1-mediated ECM deposition repression contributes to keloid pathogenesis, and the identified mechanism and related molecules provide potential targets for keloid treatment in the future.
Collapse
Affiliation(s)
- Jing-Jing Gu
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Cheng-Cheng Deng
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Qing-Lan Feng
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Jun Liu
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Ding-Heng Zhu
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Qing Cheng
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Zhili Rong
- Dermatology Hospital, Southern Medical University, Guangzhou, China; Cancer Research Institute, School of Basic Medical Sciences, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Southern Medical University, Guangzhou, China
| | - Bin Yang
- Dermatology Hospital, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
9
|
Pigeaud KE, Rietveld ML, Witvliet AF, Hogervorst JMA, Zhang C, Forouzanfar T, Bravenboer N, Schoenmaker T, de Vries TJ. The Effect of Sclerostin and Monoclonal Sclerostin Antibody Romosozumab on Osteogenesis and Osteoclastogenesis Mediated by Periodontal Ligament Fibroblasts. Int J Mol Sci 2023; 24:ijms24087574. [PMID: 37108735 PMCID: PMC10145870 DOI: 10.3390/ijms24087574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/06/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Sclerostin is a bone formation inhibitor produced by osteocytes. Although sclerostin is mainly expressed in osteocytes, it was also reported in periodontal ligament (PDL) fibroblasts, which are cells that play a role in both osteogenesis and osteoclastogenesis. Here, we assess the role of sclerostin and its clinically used inhibitor, romosozumab, in both processes. For osteogenesis assays, human PDL fibroblasts were cultured under control or mineralizing conditions with increasing concentrations of sclerostin or romosozumab. For analyzing osteogenic capacity and alkaline phosphatase (ALP) activity, alizarin red staining for mineral deposition and qPCR of osteogenic markers were performed. Osteoclast formation was investigated in the presence of sclerostin or romosozumab and, in PDLs, in the presence of fibroblasts co-cultured with peripheral blood mononuclear cells (PBMCs). PDL-PBMC co-cultures stimulated with sclerostin did not affect osteoclast formation. In contrast, the addition of romosozumab slightly reduced the osteoclast formation in PDL-PBMC co-cultures at high concentrations. Neither sclerostin nor romosozumab affected the osteogenic capacity of PDL fibroblasts. qPCR analysis showed that the mineralization medium upregulated the relative expression of osteogenic markers, but this expression was barely affected when romosozumab was added to the cultures. In order to account for the limited effects of sclerostin or romosozumab, we finally compared the expression of SOST and its receptors LRP-4, -5, and -6 to the expression in osteocyte rich-bone. The expression of SOST, LRP-4, and LRP-5 was higher in osteocytes compared to in PDL cells. The limited interaction of sclerostin or romosozumab with PDL fibroblasts may relate to the primary biological function of the periodontal ligament: to primarily resist bone formation and bone degradation to the benefit of an intact ligament that is indented by every chew movement.
Collapse
Affiliation(s)
- Karina E Pigeaud
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Melanie L Rietveld
- Amsterdam University College, University of Amsterdam and Vrije Universiteit, Science Park 113, 1098 XG Amsterdam, The Netherlands
| | - Aster F Witvliet
- Amsterdam University College, University of Amsterdam and Vrije Universiteit, Science Park 113, 1098 XG Amsterdam, The Netherlands
| | - Jolanda M A Hogervorst
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 LA Amsterdam, The Netherlands
| | - Chen Zhang
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 LA Amsterdam, The Netherlands
- Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Tim Forouzanfar
- Oral Pathology and 3D Innovation Lab, Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 LA Amsterdam, The Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Teun J de Vries
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| |
Collapse
|
|
10
|
Wang S, Li L, Cook C, Zhang Y, Xia Y, Liu Y. A potential fate decision landscape of the TWEAK/Fn14 axis on stem and progenitor cells: a systematic review. Stem Cell Res Ther 2022; 13:270. [PMID: 35729659 PMCID: PMC9210594 DOI: 10.1186/s13287-022-02930-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/19/2022] [Indexed: 11/21/2022] Open
Abstract
Stem and progenitor cells (SPCs) possess self-remodeling ability and differentiation potential and are responsible for the regeneration and development of organs and tissue systems. However, the precise mechanisms underlying the regulation of SPC biology remain unclear. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) acts on miscellaneous cells via binding to fibroblast growth factor-inducible 14 (Fn14) and exerts pleiotropic functions in the regulation of divergent stem cell fates. TWEAK/Fn14 signaling can regulate the proliferation, differentiation, and migration of multiple SPCs as well as tumorigenesis in certain contexts. Although TWEAK’s roles in modulating multiple SPCs are sparsely reported, the systemic effector functions of this multifaceted protein have not been fully elucidated. In this review, we summarized the fate decisions of TWEAK/Fn14 signaling on multiple stem cells and characterized its potential in stem cell therapy.
Collapse
Affiliation(s)
- Sijia Wang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Liang Li
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Christopher Cook
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Yufei Zhang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Yumin Xia
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China.
| | - Yale Liu
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China.
| |
Collapse
|
|
11
|
Vasiliadis ES, Evangelopoulos DS, Kaspiris A, Benetos IS, Vlachos C, Pneumaticos SG. The Role of Sclerostin in Bone Diseases. J Clin Med 2022; 11:806. [PMID: 35160258 PMCID: PMC8836457 DOI: 10.3390/jcm11030806] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 12/26/2022] Open
Abstract
Sclerostin has been identified as an important regulator of bone homeostasis through inhibition of the canonical Wnt-signaling pathway, and it is involved in the pathogenesis of many different skeletal diseases. Many studies have been published in the last few years regarding sclerostin's origin, regulation, and mechanism of action. The ongoing research emphasizes the potential therapeutic implications of sclerostin in many pathological conditions with or without skeletal involvement. Antisclerostin antibodies have recently been approved for the treatment of osteoporosis, and several animal studies and clinical trials are currently under way to evaluate the effectiveness of antisclerostin antibodies in the treatment of other than osteoporosis skeletal disorders and cancer with promising results. Understanding the exact role of sclerostin may lead to new therapeutic approaches for the treatment of skeletal disorders.
Collapse
Affiliation(s)
- Elias S. Vasiliadis
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Dimitrios-Stergios Evangelopoulos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Angelos Kaspiris
- Laboratory of Molecular Pharmacology, Division for Orthopaedic Research, School of Health Sciences, University of Patras, 26504 Rion, Greece;
| | - Ioannis S. Benetos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Christos Vlachos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Spyros G. Pneumaticos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| |
Collapse
|
|
12
|
Wu J, Liu F, Wang Z, Liu Y, Zhao X, Fang C, Leung F, Yeung KWK, Wong TM. The Development of a Magnesium-Releasing and Long-Term Mechanically Stable Calcium Phosphate Bone Cement Possessing Osteogenic and Immunomodulation Effects for Promoting Bone Fracture Regeneration. Front Bioeng Biotechnol 2022; 9:803723. [PMID: 35087804 PMCID: PMC8786730 DOI: 10.3389/fbioe.2021.803723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/20/2021] [Indexed: 12/21/2022] Open
Abstract
Bone grafts are commonly used for the treatment of critical sized bone defects. Since the supply of autologous bone is insufficient, allogeneic bone grafts have been used most of the time. However, the poor osteogenic property of allogeneic bone grafts after pretreatment results in delayed union, non-union, or even occasional deformity. Calcium phosphate cement (CPC) is one of the most promising bone filling materials due to its good biocompatibility and similar chemical components as natural bone. However, clinical applications of CPC were hampered by limited osteogenic effects, undesired immune response which results in resorption, and poor mechanical stability in vivo. Magnesium (Mg) has been proven to trigger bone regeneration through modulating cell behaviors of mesenchymal stem cells and macrophages significantly. Unfortunately, the degradation raters of pure Mg and Mg oxide are extremely fast, resulting in early collapse of Mg contained CPC. In this study, we developed a novel magnesium contained calcium phosphate bone cement (Mg-CPC), possessing long-term mechanical stability and osteogenic effects through sustained release of Mg. Furthermore, in vitro studies showed that Mg-CPC had no cytotoxic effects on hBMMSCs and macrophage RAW 264.7, and could enhance the osteogenic differentiation as determined by alkaline phosphate (ALP) activity and calcium nodule staining, as well as suppress the inflammatory as determined by expression of anti-inflammatory cytokine IL-1RA. We also found that Mg-CPC promoted new bone formation and bone maturation in vivo. These results suggest that Mg-CPC should be a good substitute material for bone grafts in clinical use.
Collapse
Affiliation(s)
- Jun Wu
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Feihong Liu
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Zejin Wang
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yuan Liu
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xiaoli Zhao
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Christian Fang
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Frankie Leung
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Kelvin W. K. Yeung
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- *Correspondence: Kelvin W. K. Yeung, ; Tak Man Wong,
| | - Tak Man Wong
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- *Correspondence: Kelvin W. K. Yeung, ; Tak Man Wong,
| |
Collapse
|
|
13
|
Ivanova MM, Dao J, Kasaci N, Friedman A, Noll L, Goker-Alpan O. Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease. Front Endocrinol (Lausanne) 2022; 13:1029130. [PMID: 36506070 PMCID: PMC9730525 DOI: 10.3389/fendo.2022.1029130] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/25/2022] [Indexed: 11/25/2022] Open
Abstract
Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson's linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.
Collapse
|
|
14
|
Yang S, Li Y, Liu C, Wu Y, Wan Z, Shen D. Pathogenesis and treatment of wound healing in patients with diabetes after tooth extraction. Front Endocrinol (Lausanne) 2022; 13:949535. [PMID: 36213270 PMCID: PMC9538860 DOI: 10.3389/fendo.2022.949535] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes mellitus is a common systematic chronic disease amongst dental patients. The elevated glucose microenvironment can prolong the healing of tooth extraction sockets. Therefore, the promotion of healing up tooth extraction sockets is of great clinical importance to the patients with diabetes mellitus. The current evidence indicates the mechanism of the recovery period of extraction sockets in hyperglycaemia conditions from physiological, inflammation, immune, endocrine and neural aspects. New advancements have been made in varied curative approaches and drugs in the management of wound healing of tooth extraction sockets in diabetes. However, most of the interventions are still in the stage of animal experiments, and whether it can be put into clinical application still needs further explorations. Specifically, our work showed topical administration of plasma-rich growth factor, advanced platelet-rich fibrin, leukocyte- and platelet-rich fibrin and hyaluronic acid as well as maxillary immediate complete denture is regarded as a promising approach for clinical management of diabetic patients requiring extractions. Overall, recent studies present a blueprint for new advances in novel and effective approaches for this worldwide health ailment and tooth extraction sockets healing.
Collapse
|
|
15
|
Cordido A, Nuñez-Gonzalez L, Martinez-Moreno JM, Lamas-Gonzalez O, Rodriguez-Osorio L, Perez-Gomez MV, Martin-Sanchez D, Outeda P, Chiaravalli M, Watnick T, Boletta A, Diaz C, Carracedo A, Sanz AB, Ortiz A, Garcia-Gonzalez MA. TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 2021; 32:1913-1932. [PMID: 34155062 PMCID: PMC8455272 DOI: 10.1681/asn.2020071094] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 03/06/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. METHODS To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. RESULTS Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. CONCLUSIONS This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.
Collapse
Affiliation(s)
- Adrian Cordido
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Nuñez-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Julio M. Martinez-Moreno
- Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Olaya Lamas-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Laura Rodriguez-Osorio
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Maria Vanessa Perez-Gomez
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Diego Martin-Sanchez
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Patricia Outeda
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Marco Chiaravalli
- Division of Genetics and Cell Biology, Molecular Basis of Cystic Kidney Disorders Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)–San Raffaele Scientific Institute, Milan, Italy
| | - Terry Watnick
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | | | - Candido Diaz
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Nephrology Service, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Angel Carracedo
- Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Galician Public Foundation of Genomic Medicine, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Center in Network of Rare Diseases (CIBERER), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana B. Sanz
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Alberto Ortiz
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Miguel A. Garcia-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Galician Public Foundation of Genomic Medicine, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| |
Collapse
|
|
16
|
Tsourdi E, Yu EW, Jan de Beur SM, Drake MT. Vaccination for Coronavirus Disease 2019 (COVID-19) and Relationship to Osteoporosis Care: Current Evidence and Suggested Approaches. J Bone Miner Res 2021; 36:1042-1047. [PMID: 33831269 PMCID: PMC8249992 DOI: 10.1002/jbmr.4304] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023]
Abstract
The development of coronavirus disease 2019 (COVID-19) vaccines has proceeded at an unprecedented pace, with numerous trials conducted simultaneously across the world as a result of massive technological and financial resource expenditures. With multiple vaccines having now received regulatory approval, public health efforts to promote widespread vaccine dissemination are currently underway. There has been particular emphasis placed on vaccination of older populations, the age group in which COVID-19 infection has been most lethal. However, such widespread vaccination approaches have necessarily raised important questions related to potential interactions with underlying diseases and concomitant treatments among persons to be vaccinated. Osteoporosis is a chronic condition marked by reduced bone strength and an associated increased risk for fracture that generally requires sustained medical intervention(s). Osteoporosis is neither associated with a higher risk of COVID-19 infection nor by more pronounced disease severity following infection, such that individuals with osteoporosis need not be more highly prioritized for COVID-19 vaccination. Osteoporosis therapies do not interfere with the efficacy or side effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination. Depending on the specific drug profile within an anti-osteoporosis medication category, minor adjustments to the timing of drug administration may be considered with respect to the patient's COVID-19 vaccination schedule. Herein we provide practical recommendations for the care of patients requiring treatment for osteoporosis in the setting of COVID-19 vaccination. © 2021 American Society for Bone and Mineral Research (ASBMR).
Collapse
Affiliation(s)
- Elena Tsourdi
- Department of Medicine III, Universitätsklinikum Dresden, Dresden, Germany.,Center for Healthy Aging, Universitätsklinikum Dresden, Dresden, Germany
| | - Elaine W Yu
- Endocrine Unit, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Suzanne M Jan de Beur
- Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthew T Drake
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
17
|
Fayed A, Soliman A, Elgohary R. Measuring Serum Sclerostin in Egyptian Patients With Systemic Lupus Erythematosus and Evaluating Its Effect on Disease Activity: A Case-Control Study. J Clin Rheumatol 2021; 27:161-167. [PMID: 31895114 DOI: 10.1097/rhu.0000000000001256] [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: 11/26/2022]
Abstract
OBJECTIVE Sclerostin is an osteocyte-secreted protein that downregulates bone formation by blocking the Wnt/β-catenin signaling pathway. Sclerostin can be induced by inflammation, and high levels have been reported in patients with proteinuria and renal impairment. Studies evaluating the role of sclerostin in systemic lupus erythematosus (SLE) patients are scarce. This study aims to measure serum sclerostin in SLE patients and correlate its level with bone biomarkers and disease activity, particularly in lupus nephritis and arthritis. Finally, we evaluated factors that may predict sclerostin concentrations. METHODS This cross-sectional, case-control study was conducted from May 2017 to April 2018. Serum sclerostin was measured by enzyme-linked immunosorbent assay in 100 SLE patients, including 50 patients with current lupus nephritis and 27 patients with current arthritis, as well as in 50 healthy controls. Correlation analysis of serum sclerostin with demography, bone biomarkers, and disease activity in SLE patients was carried out. RESULTS Sclerostin levels were significantly elevated in SLE patients, particularly those with lupus nephritis, compared with healthy controls. Higher levels were identified in patients without arthritis compared with those with; however, the former group had more proteinuria and renal impairment. Significant correlations were observed between sclerostin levels and serum creatinine, proteinuria, consumed C3 and C4 complement, and corrected Ca. Using multiple linear regression, proteinuria was the only significant predictor for serum sclerostin in SLE patients. CONCLUSIONS This study is the first to report that serum sclerostin is associated with proteinuria in SLE patients and could be used as a valuable biomarker for lupus nephritis.
Collapse
Affiliation(s)
| | | | - Rasmia Elgohary
- Rheumatology and Clinical Immunology Unit, Internal Medicine Department, Kasr Alainy School of Medicine, Cairo University, Cairo, Egypt
| |
Collapse
|
|
18
|
Maiso P, Mogollón P, Ocio EM, Garayoa M. Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression. Cancers (Basel) 2021; 13:2542. [PMID: 34067236 PMCID: PMC8196907 DOI: 10.3390/cancers13112542] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/16/2021] [Accepted: 05/19/2021] [Indexed: 01/01/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment.
Collapse
Affiliation(s)
- Patricia Maiso
- University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria, 39008 Santander, Spain
| | - Pedro Mogollón
- Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain; (P.M.); (M.G.)
| | - Enrique M. Ocio
- University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria, 39008 Santander, Spain
| | - Mercedes Garayoa
- Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain; (P.M.); (M.G.)
| |
Collapse
|
|
19
|
The Expression and Function of Metastases Associated Lung Adenocarcinoma Transcript-1 Long Non-Coding RNA in Subchondral Bone and Osteoblasts from Patients with Osteoarthritis. Cells 2021; 10:cells10040786. [PMID: 33916321 PMCID: PMC8066176 DOI: 10.3390/cells10040786] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 02/02/2023] Open
Abstract
Metastasis Associated Lung Adenocarcinoma Transcript-1 (MALAT1) is implicated in regulating the inflammatory response and in the pathology of several chronic inflammatory diseases, including osteoarthritis (OA). The purpose of this study was to examine the relationship between OA subchondral bone expression of MALAT1 with parameters of joint health and biomarkers of joint inflammation, and to determine its functional role in human OA osteoblasts. Subchondral bone and blood were collected from hip and knee OA patients (n = 17) and bone only from neck of femur fracture patients (n = 6) undergoing joint replacement surgery. Cytokines were determined by multiplex assays and ELISA, and gene expression by qPCR. MALAT1 loss of function was performed in OA patient osteoblasts using locked nucleic acids. The osteoblast transcriptome was analysed by RNASeq and pathway analysis. Bone expression of MALAT1 positively correlated to serum DKK1 and galectin-1 concentrations, and in OA patient osteoblasts was induced in response to IL-1β stimulation. Osteoblasts depleted of MALAT1 exhibited differential expression (>1.5 fold change) of 155 genes, including PTGS2. Both basal and IL-1β-mediated PGE2 secretion was greater in MALAT1 depleted osteoblasts. The induction of MALAT1 in human OA osteoblasts upon inflammatory challenge and its modulation of PGE2 production suggests that MALAT1 may play a role in regulating inflammation in OA subchondral bone.
Collapse
|
|
20
|
Osteoporosis Treatment with Anti-Sclerostin Antibodies-Mechanisms of Action and Clinical Application. J Clin Med 2021; 10:jcm10040787. [PMID: 33669283 PMCID: PMC7920044 DOI: 10.3390/jcm10040787] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/30/2021] [Accepted: 02/13/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures and significant long-term disability. Although both anti-resorptive treatments and osteoanabolic drugs, such as parathyroid hormone analogues, are effective in fracture prevention, limitations exist due to lack of compliance or contraindications to these drugs. Thus, there is a need for novel potent therapies, especially for patients at high fracture risk. Romosozumab is a monoclonal antibody against sclerostin with a dual mode of action. It enhances bone formation and simultaneously suppresses bone resorption, resulting in a large anabolic window. In this opinion-based narrative review, we highlight the role of sclerostin as a critical regulator of bone mass and present human diseases of sclerostin deficiency as well as preclinical models of genetically modified sclerostin expression, which led to the development of anti-sclerostin antibodies. We review clinical studies of romosozumab in terms of bone mass accrual and anti-fracture activity in the setting of postmenopausal and male osteoporosis, present sequential treatment regimens, and discuss its safety profile and possible limitations in its use. Moreover, an outlook comprising future translational applications of anti-sclerostin antibodies in diseases other than osteoporosis is given, highlighting the clinical significance and future scopes of Wnt signaling in these settings.
Collapse
|
|
21
|
Huang Y, Wang X, Wu F, Lu Y, Liang G, Liu A. The Possible Role of Sclerostin in the Pathogenesis of Tympanosclerosis. Audiol Neurootol 2021; 26:102-110. [PMID: 33508832 DOI: 10.1159/000508692] [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: 12/10/2019] [Accepted: 05/14/2020] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE The aim of this study was to investigate sclerostin (SOST) expression in a rat model of experimental tympanosclerosis (TS) and its possible role in the formation of TS. MATERIALS AND METHODS Thirty-four SD rats were randomly divided into 2 groups: experimental group (n = 17) and normal group (n = 17). The left tympanic cavities in the experimental group were inoculated with methicillin-resistant Staphylococcus aureus. The changes of tympanic membranes were examined and recorded under otoendoscope. Haematoxylin-eosin staining was adopted to detect the morphological changes in the tympanic membrane and middle ear mucosa. Immunohistochemistry and Western blot analysis were used to observe the expression of SOST, Wnt3a, β-catenin, and P-ERK1/2. RESULTS In the experimental group, sclerotic lesions were observed in 54.5% ears in the end of 6 weeks. Morphological changes such as mucosa incrassation, inflammatory cells infiltration, fibrous tissue proliferation, and interstitial tissue incrassation prominently appeared in the tympanic membrane and middle ear mucosa. SOST protein was mainly distributed in the cytoplasm of epithelial cells and gland cells, the expression of which increased significantly in the calcified experimental ears. In addition, expression levels of Wnt3a, β-catenin, and P-ERK1/2 increased significantly in the calcified group too. CONCLUSION The upregulated expression level of SOST may be involved in the formation of TS, first, through the pro-phosphorylation of ERK1/2 in the inflammatory stage, and then through the enhancement of Wnt3a in the osteogenic stage.
Collapse
Affiliation(s)
- Yu Huang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xiansong Wang
- Department of Huazhong, University of Science and Technology, Wuhan, China
| | - Fashuai Wu
- Department of Xiehe Hospital, Wuhan, China
| | - Yuqing Lu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Gengtian Liang
- Department of The Third Hospital of Wuhan City, Wuhan, China
| | - Aiguo Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China,
| |
Collapse
|
|
22
|
Eid A, Issa Y, Mohamed A, Badran F. Interleukin-9 and soluble tumor necrosis factor-like weak inducer of apoptosis in serum and suction blister fluid of nonsegmental vitiligo patients: Relation to disease severity. DERMATOL SIN 2021. [DOI: 10.4103/ds.ds_44_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
23
|
Wyskida K, Franik G, Owczarek AJ, Choręza P, Kocełak P, Madej P, Chudek J, Olszanecka-Glinianowicz M. Plasma sclerostin levels are associated with nutritional status and insulin resistance but not hormonal disturbances in women with polycystic ovary syndrome. Arch Gynecol Obstet 2020; 302:1025-1031. [PMID: 32592042 PMCID: PMC7471162 DOI: 10.1007/s00404-020-05656-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 06/18/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the circulating sclerostin levels with nutritional status, insulin resistance and hormonal disturbances in women with polycystic ovary syndrome (PCOS). PATIENTS AND METHODS The cross-sectional study involved 98 PCOS inpatients (20 normal weight, 17 overweight and 61 obese) with stable body mass. Body composition was assessed by bioimpedance method in addition to anthropometric measurements (body mass and height). Serum/plasma concentrations of glucose, insulin (with the calculation of homeostatic model assessment insulin resistance-HOMA-IR), estradiol, total testosterone, sex hormone-binding globulin (SHBG) and sclerostin were measured. Free androgen index (FAI) and estradiol/testosterone index were calculated. RESULTS Plasma sclerostin levels were significantly higher in obese [0.61 (interquartile range 0.53-0.77) ng/mL] than in overweight [0.53 (0.49-0.57) ng/mL] and normal weight [0.49 (0.42-0.54) ng/mL] groups. Plasma sclerostin levels were significantly higher in the subgroup with insulin resistance [0.65 (interquartile range 0.53-0.77) vs. 0.52 (0.46-0.58) ng/mL; p < 0.001], while similar concentrations were observed in subgroups with FAI below and above median. Plasma sclerostin levels variability were explained by BMI (r = 0.40), the percentage of body fat (r = 0.40) and HOMA-IR values (r = 0.34) in multivariable models. CONCLUSIONS Circulating sclerostin levels in women with PCOS are related to nutritional status and insulin resistance, but not to sex hormone disturbances.
Collapse
Affiliation(s)
- Katarzyna Wyskida
- Health Promotion and Obesity Management Unit, Department of Pathophysiology, Medical Faculty in Katowice, The Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland
| | - Grzegorz Franik
- Department of Gynecological Endocrinology, Medical Faculty in Katowice, The Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland
| | - Aleksander Jerzy Owczarek
- Department of Statistics, Department of Instrumental Analysis, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, Ostrogórska 30, 41-209, Sosnowiec, Poland
| | - Piotr Choręza
- Department of Statistics, Department of Instrumental Analysis, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, Ostrogórska 30, 41-209, Sosnowiec, Poland
| | - Piotr Kocełak
- Pathophysiology Unit, Department of Pathophysiology, Medical Faculty in Katowice, The Medical University of Silesia, Medyków 18, Katowice, 40-752, Poland
| | - Paweł Madej
- Department of Gynecological Endocrinology, Medical Faculty in Katowice, The Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland
| | - Jerzy Chudek
- Pathophysiology Unit, Department of Pathophysiology, Medical Faculty in Katowice, The Medical University of Silesia, Medyków 18, Katowice, 40-752, Poland
- Department of Internal Medicine and Oncological Chemotherapy, Medical Faculty in Katowice, The Medical University of Silesia, Reymonta 8, Katowice, 40-027, Poland
| | - Magdalena Olszanecka-Glinianowicz
- Health Promotion and Obesity Management Unit, Department of Pathophysiology, Medical Faculty in Katowice, The Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland.
| |
Collapse
|
|
24
|
Kouvelioti R, Kurgan N, Falk B, Ward WE, Josse AR, Klentrou P. Cytokine and Sclerostin Response to High-Intensity Interval Running versus Cycling. Med Sci Sports Exerc 2020; 51:2458-2464. [PMID: 31246713 DOI: 10.1249/mss.0000000000002076] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE This study examined whether the exercise-induced changes in inflammatory cytokines differ between impact and no-impact high-intensity interval exercise, and whether they are associated with postexercise changes in sclerostin. METHODS Thirty-eight females (n = 19, 22.6 ± 2.7 yr) and males (n = 19, 22.3 ± 2.4 yr) performed two high-intensity interval exercise trials in random order (crossover design): running on a treadmill and cycling on a cycle ergometer. Trials consisted of eight repetitions of 1 min running or cycling at ≥90% maximal heart rate, separated by 1 min passive recovery intervals. Blood was collected preexercise and 5 min, 1 h, 24 h, and 48 h postexercise, and it was analyzed for serum levels of interleukins (IL-1β, IL-6, and IL-10), tumor necrosis factor alpha (TNF-α), and sclerostin. RESULTS Inflammatory cytokines significantly increased over time in both sexes with some differences between trials. Specifically, IL-1β significantly increased from pre- to 5 min after both trials (23%, P < 0.05), IL-6 increased 1 h after both trials (39%, P < 0.05), IL-10 was elevated 5 min after running (20%, P < 0.05) and 1 h after both running and cycling (41% and 64%, respectively, P < 0.05), and TNF-α increased 5 min after running (10%, P < 0.05). Sclerostin increased 5 min after both trials, with a greater increase in males than that in females (62 vs 32 pg·mL in running, P = 0.018; 63 vs 30 pg·mL in cycling, P = 0.004). In addition, sclerostin was significantly correlated with the corresponding changes in inflammatory cytokines, and 34% of the variance in its postexercise gain score (Δ) was explained by sex and the corresponding gain scores in TNF-α, which was the strongest predictor. CONCLUSION A single bout of either impact or no-impact high-intensity exercise induces changes in inflammatory cytokines, which are associated with the postexercise increase in sclerostin.
Collapse
Affiliation(s)
- Rozalia Kouvelioti
- Faculty of Applied Health Sciences, Department of Kinesiology, Brock University, St. Catharines, ON, CANADA
| | - Nigel Kurgan
- Faculty of Applied Health Sciences, Department of Kinesiology, Brock University, St. Catharines, ON, CANADA
| | - Bareket Falk
- Faculty of Applied Health Sciences, Department of Kinesiology, Brock University, St. Catharines, ON, CANADA.,Faculty of Applied Health Sciences, Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, CANADA
| | - Wendy E Ward
- Faculty of Applied Health Sciences, Department of Kinesiology, Brock University, St. Catharines, ON, CANADA.,Faculty of Applied Health Sciences, Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, CANADA
| | - Andrea R Josse
- Faculty of Applied Health Sciences, Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, CANADA.,Faculty of Health, School of Kinesiology and Health Science, York University, Toronto, ON, CANADA
| | - Panagiota Klentrou
- Faculty of Applied Health Sciences, Department of Kinesiology, Brock University, St. Catharines, ON, CANADA.,Faculty of Applied Health Sciences, Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, CANADA
| |
Collapse
|
|
25
|
Wang T, Yu X, He C. Pro-inflammatory Cytokines: Cellular and Molecular Drug Targets for Glucocorticoid-induced-osteoporosis via Osteocyte. Curr Drug Targets 2020; 20:1-15. [PMID: 29618305 DOI: 10.2174/1389450119666180405094046] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 03/11/2018] [Accepted: 03/21/2018] [Indexed: 02/08/2023]
Abstract
Glucocorticoids are widely used to treat varieties of allergic and autoimmune diseases, however, long-term application results in glucocorticoid-induced osteoporosis (GIOP). Inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) play important regulatory roles in bone metabolism, but their roles in GIOP remain largely unknown. Osteocytes can modulate the formation and function of both osteoblasts and osteoclasts, directly via gap junctions, or indirectly by transferring molecule signaling. Apoptotic osteocytes release RANKL, HMGB1 and pro-inflammatory cytokines to stimulate osteoclastogenesis. Moreover, osteocytes can secrete FGF23 to regulate bone metabolism. Exposure to high levels of GCs can drive osteocyte apoptosis and influence gap junctions, leading to bone loss. GCs treatment is regarded to produce more FGF23 to inhibit bone mineralization. GCs also disrupt the vascular to decrease osteocyte feasibility and mineral appositional rate, resulting in a decline in bone strength. Apoptotic bodies from osteocytes induced by GCs treatment can enhance production of TNF-α and IL-6. On the other hand, TNF-α and IL-6 show synergistic effects by altering osteocytes signaling towards osteoclasts and osteoblasts. In addition, TNF-α can induce osteocyte apoptosis and attribute to a worsened bone quality in GCs. IL-6 and osteocytes may interact with each other. Therefore, we hypothesize that GCs regulate osteocyteogenesis through TNF-α and IL-6, which are highly expressed around osteocyte undergoing apoptosis. In the present review, we summarized the roles of osteocytes in regulating osteoblasts and osteoclasts. Furthermore, the mechanism of GCs altered relationship between osteocytes and osteoblasts/osteoclasts. In addition, we discussed the roles of TNF-α and IL-6 in GIOP by modulating osteocytes. Lastly, we discussed the possibility of using pro-inflammatory signaling pathway as therapeutic targets to develop drugs for GIOP.
Collapse
Affiliation(s)
- Tiantian 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.,Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 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
| |
Collapse
|
|
26
|
Ying J, Wang P, Ding Q, Shen J, O'Keefe RJ, Chen D, Tong P, Jin H. Peripheral Blood Stem Cell Therapy Does Not Improve Outcomes of Femoral Head Osteonecrosis With Cap-Shaped Separated Cartilage Defect. J Orthop Res 2020; 38:269-276. [PMID: 31520480 DOI: 10.1002/jor.24471] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 09/03/2019] [Indexed: 02/04/2023]
Abstract
A combination treatment with porous tantalum rod implantation and intra-arterial infusion of peripheral blood stem cells (PBSCs) provides a promise for treating early and intermediate stages of osteonecrosis of the femoral head (ONFH). However, its clinical indications and application restrictions remain unclear. This study aims to determine the clinical, histological, and radiological outcomes of a combination treatment using mechanical support and a targeted intra-arterial infusion of PBSCs for painful ONFH with a cap-shaped separation (CSS) cartilage defect. Compared with the standard pain management (control group), this combination treatment did not improve the Harris Hip Score (HHS) at 36 months. Micro-CT and histologic analyses showed severe focal destruction in all CSS-ONFH femoral heads in both the combination and control groups. Femoral heads showed a higher percentage of bone lesions in the combination treatment group than in the control group. There was no significant difference in osteoclast number in the subchondral bone areas between the two groups. A high level of expression of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, was detected in blood vessels around the subchondral bone in both groups. The RANKL/OPG (receptor activator of the nuclear factor-kB ligand/osteoprotegerin) ratio was also similar between the control and combination treatment groups. Our results indicate that this combination treatment is not an effective method for the treatment of patients with painful CSS-ONFH. Moreover, this combination treatment did not inhibit inflammatory osteoclastogenesis in patients with more advanced disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:269-276, 2020.
Collapse
Affiliation(s)
- Jun Ying
- The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, China.,Department of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, China.,Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri
| | - Pinger Wang
- Department of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, China
| | - Quanwei Ding
- The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, China.,Department of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, China
| | - Jie Shen
- Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri
| | - Regis J O'Keefe
- Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri
| | - Di Chen
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, 60612
| | - Peijian Tong
- Department of Orthopaedic Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, Zhejiang Province, China
| | - Hongting Jin
- Department of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, China
| |
Collapse
|
|
27
|
Evaluating the role of serum sclerostin as an indicator of activity and damage in Egyptian patients with rheumatoid arthritis: university hospital experience. Clin Rheumatol 2019; 39:1121-1130. [DOI: 10.1007/s10067-019-04878-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 11/25/2019] [Accepted: 12/04/2019] [Indexed: 12/15/2022]
|
|
28
|
Liao C, Wang Y, Ou Y, Wu Y, Zhou Y, Liang S. Effects of sclerostin on lipopolysaccharide-induced inflammatory phenotype in human odontoblasts and dental pulp cells. Int J Biochem Cell Biol 2019; 117:105628. [PMID: 31639458 DOI: 10.1016/j.biocel.2019.105628] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 10/07/2019] [Accepted: 10/10/2019] [Indexed: 01/07/2023]
Abstract
Previously we have demonstrated that sclerostin inhibits stress-induced odontogenic differentiation of odontoblasts and accelerates senescence of dental pulp cells (DPCs) Odontoblasts and DPCs are main functioning cells for inflammation resistance and tissue regeneration in dentine-pulp complex. Sclerostin is relevant for systemic inflammation and chronic periodontitis processes, but its effects on dental pulp inflammation remains unclear. In this study, we found that sclerostin expression of odontoblasts was elevated in lipopolysaccharide-induced inflammatory environment, and exogenous sclerostin increased the production of pro-inflammatory cytokines in inflamed odontoblasts. Furthermore, sclerostin activated the NF-κB signaling pathway in inflamed odontoblasts and the NF-κB inhibitor reversed the exaggerative effects of sclerostin on the pro-inflammatory cytokines production. Additionally, sclerostin promoted adhesion and migration of inflamed DPCs, while inhibiting odontoblastic differentiation of inflamed DPCs. Sclerostin also might enhance pulpal angiogenesis. Taken together, it can therefore be inferred that sclerostin is upregulated in inflamed odontoblasts under pulpal inflammatory condition to enhance inflammatory responses in dentine-pulp complex and impair reparative dentinogenesis. This indicates that sclerostin inhibition might be a therapeutic target for anti-inflammation and pro-regeneration during dental pulp inflammation.
Collapse
Affiliation(s)
- Chufang Liao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China
| | - Yining Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China; Department of Prosthodontics, Hospital of Stomatology, Wuhan University, China
| | - Yanjing Ou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China
| | - Yun Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China
| | - Yi Zhou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China; Department of Prosthodontics, Hospital of Stomatology, Wuhan University, China
| | - Shanshan Liang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China; Department of Prosthodontics, Hospital of Stomatology, Wuhan University, China.
| |
Collapse
|
|
29
|
Abstract
PURPOSE OF REVIEW Osteocytes are responsible for mechanosensing and mechanotransduction in bone and play a crucial role in bone homeostasis. They are embedded in a calcified collagenous matrix and connected with each other through the lacuno-canalicular network. Due to this specific native environment, it is a challenge to isolate primary osteocytes without losing their specific characteristics in vitro. This review summarizes the commonly used and recently established models to study the function of osteocytes in vitro. RECENT FINDINGS Osteocytes are mostly studied in monolayer culture, but recently, 3D models of osteocyte-like cells and primary osteocytes in vitro have been established as well. These models mimic the native environment of osteocytes and show superior osteocyte morphology and behavior, enabling the development of human disease models. Osteocyte-like cell lines as well as primary osteocytes isolated from bone are widely used to study the role of osteocytes in bone homeostasis. Both cells lines and primary cells are cultured in 2D-monolayer and 3D-models. The use of these models and their advantages and shortcomings are discussed in this review.
Collapse
Affiliation(s)
- Chen Zhang
- Department of Oral Cell Biology, Amsterdam Movement Sciences, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Clinical Chemistry, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Astrid D Bakker
- Department of Oral Cell Biology, Amsterdam Movement Sciences, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jenneke Klein-Nulend
- Department of Oral Cell Biology, Amsterdam Movement Sciences, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- Department of Internal Medicine, Division of Endocrinology and Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands.
| |
Collapse
|
|
30
|
Sakamoto E, Kido JI, Takagi R, Inagaki Y, Naruishi K, Nagata T, Yumoto H. Advanced glycation end-product 2 and Porphyromonas gingivalis lipopolysaccharide increase sclerostin expression in mouse osteocyte-like cells. Bone 2019; 122:22-30. [PMID: 30735798 DOI: 10.1016/j.bone.2019.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 01/23/2019] [Accepted: 02/04/2019] [Indexed: 02/06/2023]
Abstract
Sclerostin is a secreted glycoprotein that is mainly expressed in osteocytes, exerts negative effects on bone formation, and is present at elevated levels in diabetes mellitus (DM). Periodontitis is an infectious disease caused by periodontopathic bacteria, a complication of DM, and sometimes associated with severe inflammation and alveolar bone resorption. Advanced glycation end-products (AGEs) are a major pathogen in DM complications and adversely influence periodontitis in DM patients. In the present study, the effects of AGE2 and Porphyromonas gingivalis lipopolysaccharide (P-LPS) on the expression of sclerostin in mouse osteocyte-like cells (MLO-Y4-A2 cells) and its function in osteoblast differentiation were investigated. AGE2 and P-LPS up-regulated the expressions of receptor of AGE (RAGE) and Toll-like receptor 2 (TLR2), respectively, and significantly up-regulated that of sclerostin and interleukin 6 (IL-6) in osteocytes. Sclerostin, RAGE and TLR2 levels were synergistically increased by AGE2 and P-LPS. The siRNAs of RAGE and TLR2 significantly inhibited AGE2- and P-LPS-induced sclerostin expression. AGE2 up-regulated sclerostin expression in osteocyte-like cells via the RAGE, ERK and JNK, and NF-κB signal pathways. On the other hand, P-LPS elevated sclerostin levels via the TLR2, JNK and p38, and NF-κB signal pathways. When osteocytes pre-treated with AGE2 and P-LPS and osteoblastic cells (MC3T3-E1) were co-cultured in the medium with a sclerostin-neutralizing antibody, AGE2- and P-LPS-induced decreases in alkaline phosphatase activity and Runx2 expression in osteoblastic cells were significantly inhibited by the sclerostin-neutralizing antibody. These results suggest that AGE2 and P-LPS influence bone metabolism and inflammation through the regulation of sclerostin expression, and may aggravate periodontitis with DM.
Collapse
Affiliation(s)
- Eijiro Sakamoto
- Department of Periodontology and Endodontology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Jun-Ichi Kido
- Department of Periodontology and Endodontology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
| | - Ryosuke Takagi
- Department of Periodontology and Endodontology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yuji Inagaki
- Department of Periodontology and Endodontology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Koji Naruishi
- Department of Periodontology and Endodontology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Toshihiko Nagata
- Department of Periodontology and Endodontology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiromichi Yumoto
- Department of Periodontology and Endodontology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| |
Collapse
|
|
31
|
Liao C, Ou Y, Wu Y, Zhou Y, Liang S, Wang Y. Sclerostin inhibits odontogenic differentiation of human pulp‐derived odontoblast‐like cells under mechanical stress. J Cell Physiol 2019; 234:20779-20789. [PMID: 31025337 DOI: 10.1002/jcp.28684] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 04/02/2019] [Accepted: 04/05/2019] [Indexed: 01/13/2023]
Affiliation(s)
- Chufang Liao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education School & Hospital of Stomatology, Wuhan University Wuhan China
| | - Yanjing Ou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education School & Hospital of Stomatology, Wuhan University Wuhan China
| | - Yun Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education School & Hospital of Stomatology, Wuhan University Wuhan China
| | - Yi Zhou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education School & Hospital of Stomatology, Wuhan University Wuhan China
- Department of Prosthodontics Hospital of Stomatology, Wuhan University Wuhan China
| | - Shanshan Liang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education School & Hospital of Stomatology, Wuhan University Wuhan China
- Department of Prosthodontics Hospital of Stomatology, Wuhan University Wuhan China
| | - Yining Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education School & Hospital of Stomatology, Wuhan University Wuhan China
- Department of Prosthodontics Hospital of Stomatology, Wuhan University Wuhan China
| |
Collapse
|
|
32
|
Acharya AB, Chandrashekar A, Acharya S, Shettar L, Thakur S. Serum sTWEAK levels in chronic periodontitis and type 2 diabetes mellitus. Diabetes Metab Syndr 2019; 13:1609-1613. [PMID: 31336529 DOI: 10.1016/j.dsx.2019.03.027] [Citation(s) in RCA: 3] [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: 02/16/2019] [Accepted: 03/14/2019] [Indexed: 01/19/2023]
Abstract
AIM The two-way relationship between diabetes mellitus and periodontitis has been extensively studied with various interconnected biomarkers sharing a link. Soluble Tumour Necrosis Factor-like Weak inducer of apoptosis (sTWEAK) is gaining attention as an important mediator in chronic inflammatory diseases. Thus, the aim of this study was to detect, estimate and compare the levels of sTWEAK in the serum of health, chronic periodontitis (CP), and CP with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS Forty-five participants between 18 and 65 years were divided into groups of 15 each as Group 1: healthy, Group 2: CP, and Group 3: CP + T2DM. Clinical periodontal parameters and glycemic status were assessed. sTWEAK in serum was estimated using a commercially available ELISA kit. The data was statistically analyzed. RESULTS sTWEAK was detected in all participants. Significant differences were observed between the groups for sTWEAK; highest in health, lower in CP and lowest in CP + T2DM. In the diseased groups, the clinical and glycemic parameters correlated positively with each other, whereas sTWEAK correlated negatively with each of the parameters. CONCLUSION The literature reports lower concentrations of systemic sTWEAK in T2DM which may be comparable to our observations in CP + T2DM when compared to health and its negative correlation with all the parameters suggesting an association with both clinical periodontal parameters and glycemic levels. However, serum sTWEAK levels may not be necessarily elevated in periodontitis as previously reported, and hence has the potential to be studied extensively for clarification with its association with T2DM.
Collapse
Affiliation(s)
- Anirudh B Acharya
- Department of Periodontics, S.D.M. College of Dental Sciences & Hospital, Dharwad, 580009, Karnataka, India.
| | - Apoorva Chandrashekar
- Department of Periodontics, A.J. Shetty Institute of Dental Sciences, Mangalore, 575004, Karnataka, India
| | - Swetha Acharya
- Department of Oral Pathology & Microbiology, S.D.M. College of Dental Sciences & Hospital, Dharwad, 580009, Karnataka, India
| | - Leena Shettar
- Department of Periodontics, S.D.M. College of Dental Sciences & Hospital, Dharwad, 580009, Karnataka, India
| | - Srinath Thakur
- Department of Periodontics, S.D.M. College of Dental Sciences & Hospital, Dharwad, 580009, Karnataka, India
| |
Collapse
|
|
33
|
Sankardas PA, Lavu V, Lakakula BVKS, Rao SR. Differential expression of periostin, sclerostin, receptor activator of nuclear factor-κB, and receptor activator of nuclear factor-κB ligand genes in severe chronic periodontitis. JOURNAL OF INVESTIGATIVE AND CLINICAL DENTISTRY 2019; 10:e12369. [PMID: 30375186 DOI: 10.1111/jicd.12369] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 07/31/2018] [Indexed: 02/06/2023]
Abstract
AIM The aim of the present study was to determine and compare the expression profile of periostin (POSTN), sclerostin (SOST), receptor activator nuclear factor-κB (RANK), and RANK ligand (RANKL) genes in gingival tissue samples collected from healthy gingiva (control) and severe chronic periodontitis sites. METHODS Fifty systemically-healthy individuals was enrolled in the present case-control study. Gingival tissue samples were obtained from healthy gingiva (N = 25) and sites with severe chronic periodontitis (N = 25). Total RNA was isolated from all the tissues. cDNA conversion was then performed using a reverse transcription polymerase chain reaction (PCR) program. Real-time PCR and SYBR green method were used to determine the expression levels of SOST, POSTN, RANK, and RANKL genes. RESULTS An elevated expression (3.5-4-fold) of SOST, RANK, and RANKL genes, with a concomitant reduced expression of the POSTN gene, was identified in severe chronic periodontitis. The intergroup difference between the mean delta cyclic threshold values showed statistical significance at P<.001. CONCLUSIONS The expression profile of SOST, RANK, RANKL, and POSTN genes observed in gingival tissue samples from sites with severe chronic periodontitis and healthy gingiva suggests that the differential level of the gene expression could serve as an indicator of periodontitis progression/severity.
Collapse
Affiliation(s)
- Pooja A Sankardas
- Department of Periodontology, Faculty of Dental Sciences, Sri Ramachandra University, Chennai, Tamil Nadu, India
| | - Vamsi Lavu
- Department of Periodontology, Faculty of Dental Sciences, Sri Ramachandra University, Chennai, Tamil Nadu, India
| | | | - Suresh R Rao
- Department of Periodontology, Faculty of Dental Sciences, Sri Ramachandra University, Chennai, Tamil Nadu, India
| |
Collapse
|
|
34
|
Cao Y, Wang B, Wang D, Zhan D, Mai C, Wang P, Wei Q, Liu Y, Wang H, He W, Xu L. Expression of Sclerostin in Osteoporotic Fracture Patients Is Associated with DNA Methylation in the CpG Island of the SOST Gene. Int J Genomics 2019; 2019:7076513. [PMID: 30729116 PMCID: PMC6341240 DOI: 10.1155/2019/7076513] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/26/2018] [Accepted: 10/11/2018] [Indexed: 01/17/2023] Open
Abstract
PURPOSE SOST gene is one of the key factors in regulating bone absorption. Although there are reports showing diverse transcription factors, epigenetic modification could be responsible for regulating SOST gene expression. There is still little exploration on promoter methylation status of SOST gene in osteoporotic bone tissues. The aim of this study is to investigate the involvement of CpG methylation in regulation of SOST expression in patients with primary osteoporosis. METHODS The diagnosis of osteoporosis was established on the basis of dual energy X-ray absorptiometry to measure BMD. All femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we checked the relative expression levels of SOST by quantitative real-time PCR and western blot. Also, immunohistochemical staining was performed to observe the expression of SOST protein in the bone samples. The genomic DNA of non-OPF (non-osteoporotic fracture bone tissues) and OPF (osteoporotic fracture bone tissues) were treated by bisulfite modification, and methylation status of CpG sites in the CpG island of SOST gene promoter was determined by DNA sequencing. RESULTS SOST gene expression in the non-OPF group was lower than that in OPF group. Bisulfite sequencing result showed that SOST gene promoter was slightly demethylated in the OPF group, as compared with non-OPF group. CONCLUSION Our study demonstrated that DNA methylation influenced the transcriptional expression of SOST gene, which probably may play an important role in the pathogenesis of primary osteoporosis.
Collapse
Affiliation(s)
- Yanming Cao
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Bin Wang
- Department of Orthopedics, People's Hospital of Sanshui, Foshan, China
| | - Ding Wang
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dongxiang Zhan
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Caiyuan Mai
- Department of Obstetrics, Guangdong Women and Children's Hospital, Guangzhou 510010, China
| | - Peng Wang
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qiushi Wei
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yamei Liu
- Departments of Diagnostics of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Haibin Wang
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei He
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liangliang Xu
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Laboratory of Orthopaedics & Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
35
|
Cheng Q, Wu X, Du Y, Hong W, Tang W, Li H, Chen M, Zheng S. Levels of serum sclerostin, FGF-23, and intact parathyroid hormone in postmenopausal women treated with calcitriol. Clin Interv Aging 2018; 13:2367-2374. [PMID: 30532527 PMCID: PMC6247960 DOI: 10.2147/cia.s186199] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective This study aimed to determine the effect of calcitriol on serum concentrations of fibroblast growth factor-23 (FGF-23), sclerostin, intact parathyroid hormone (PTH), and handgrip strength in postmenopausal women with low bone mass. Methods A randomized, double-blind controlled trial was carried out among 141 postmenopausal women with low bone mass. Participants were randomized into two groups: 75 participants received calcitriol 0.5 µg/day and 66 participants received a placebo for 12 weeks. Results After 12-week calcitriol treatment, significant decreases in serum intact PTH (P=0.035) and sclerostin (P=0.039), as well as significant increases in serum creatinine (P=0.027), uric acid (P=0.032), 24-hour urinary calcium (P=0.0026), and left handgrip strength (P=0.03), were observed, compared to placebo group. Level of serum sclerostin was weakly but significantly positively correlated with serum PTH (r=0.277; P=0.01) and negatively correlated with 24-hour urinary calcium (r=-0.221; P=0.04) and left handgrip strength (r=-0.338; P=0.03) after calcitriol treatment. Multiple regression analysis demonstrated that decrease in serum sclerostin was associated with decrease in PTH serum level after calcitriol treatment (OR, 7.90; 95% CI, 2.28-27.42; P=0.002). However, no significant change in FGF-23 level was observed after calcitriol treatment. Conclusion Calcitriol treatment yields a considerable decrease in serum sclerostin and significant increase of handgrip strength, and the change in serum sclerostin is regulated by serum PTH and by muscle strength.
Collapse
Affiliation(s)
- Qun Cheng
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Shanghai, China, .,Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China, .,National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China,
| | - Xiaoxing Wu
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Shanghai, China, .,Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China,
| | - Yanping Du
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Shanghai, China, .,Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China, .,National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China,
| | - Wei Hong
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Shanghai, China, .,Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China, .,National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China,
| | - Wenjing Tang
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Shanghai, China, .,Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China, .,National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China,
| | - Huilin Li
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Shanghai, China, .,Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China, .,National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China,
| | - Minmin Chen
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Shanghai, China, .,Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China, .,National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China,
| | - Songbai Zheng
- National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China,
| |
Collapse
|
|
36
|
De Luna N, Suarez-Calvet X, Garicano M, Fernandez-Simon E, Rojas-García R, Diaz-Manera J, Querol L, Illa I, Gallardo E. Effect of MAPK Inhibition on the Differentiation of a Rhabdomyosarcoma Cell Line Combined With CRISPR/Cas9 Technology: An In Vitro Model of Human Muscle Diseases. J Neuropathol Exp Neurol 2018; 77:964-972. [DOI: 10.1093/jnen/nly078] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Noemí De Luna
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Xavier Suarez-Calvet
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Maialen Garicano
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Esther Fernandez-Simon
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Ricardo Rojas-García
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Jordi Diaz-Manera
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Luis Querol
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Isabel Illa
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| | - Eduard Gallardo
- Department of Neuromuscular Diseases Laboratory, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Raras
| |
Collapse
|
|
37
|
Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model. Sci Rep 2018; 8:3492. [PMID: 29472591 PMCID: PMC5823923 DOI: 10.1038/s41598-018-21886-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 02/13/2018] [Indexed: 12/20/2022] Open
Abstract
Periarticular bone loss in rheumatoid arthritis (RA) is considered to be mainly related to synovial inflammation. However, strong bone loss has also described at the time of arthritis onset. Recently, a paradoxical exacerbation of joint damage was described when blocking sclerostin in various arthritis models. Thus, we aimed to determine kinetics of bone loss and its mechanisms in the adjuvant induced arthritis (AIA) rat model of RA. AIA was induced (n = 35) or not (n = 35) at day 0. In addition to well-known arthritis at day 12, we showed with 3D-imaging and histomorphometry that bone microstructural alterations occurred early from day 8 post-induction, characterized by cortical porosity and trabecular bone loss. Active osteoclastic surfaces were increased from day 8 with RANKL upregulation. More surprisingly SOST and DKK1 were overexpressed from day 6 and followed by a dramatic decrease in bone formation from day 8. At the time of arthritis onset, SOST and DKK1 returned to control values, but frizzled related protein 1 (SFRP1), proinflammatory cytokines, and MMPs started to increase. Bone alterations before arthritis onset reinforce the hypothesis of an early bone involvement in arthritis. Kinetics of osteocyte markers expression should be considered to refine Wnt inhibitor treatment strategies.
Collapse
|
|
38
|
Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Ungprasert P. Hepatitis C virus infection and risk of osteoporotic fracture: A systematic review and meta-analysis. J Evid Based Med 2018; 11:20-25. [PMID: 29322660 DOI: 10.1111/jebm.12286] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 07/23/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND/OBJECTIVES Hepatitis C virus (HCV) infection is one of the most common causes of chronic liver disease. Several epidemiologic studies have suggested that patients with HCV infection might have a higher risk of osteoporotic fracture. However, the data are inconclusive. This systematic review and meta-analysis was conducted with the aims to summarize all available evidence. METHODS A literature search was performed using MEDLINE and EMBASE database from inception to June 2016. Studies that reported relative risks, odd ratios, or hazard ratios comparing the risk of osteoporotic fracture among HCV-infected patients versus subjects without HCV infection were included. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS Three studies with 362,285 participants met our eligibility criteria and were included in analysis. We found a significantly higher risk of osteoporotic fracture among patients with HCV infection with RR of 1.53 (95% CI 1.09 to 2.14). CONCLUSIONS Our study demonstrated an increased risk of osteoporotic fracture among HCV-infected patients. Further studies are required to clarify how this risk should be addressed in clinical practice.
Collapse
Affiliation(s)
- Karn Wijarnpreecha
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | - Charat Thongprayoon
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | | | - Patompong Ungprasert
- Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
39
|
Burr DB, Utreja A. Editorial: Wnt Signaling Related to Subchondral Bone Density and Cartilage Degradation in Osteoarthritis. Arthritis Rheumatol 2018; 70:157-161. [DOI: 10.1002/art.40382] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 11/14/2017] [Indexed: 12/16/2022]
Affiliation(s)
- David B. Burr
- Indiana University School of Medicine and Indiana University‐Purdue University–Indianapolis Indianapolis Indiana
| | - Achint Utreja
- Indiana University School of Dentistry Indianapolis Indiana
| |
Collapse
|
|
40
|
Abstract
PURPOSE OF REVIEW This review provides a summary of the current knowledge on Sost/sclerostin in cancers targeting the bone, discusses novel observations regarding its potential as a therapeutic approach to treat cancer-induced bone loss, and proposes future research needed to fully understand the potential of therapeutic approaches that modulate sclerostin function. RECENT FINDINGS Accumulating evidence shows that sclerostin expression is dysregulated in a number of cancers that target the bone. Further, new findings demonstrate that pharmacological inhibition of sclerostin in preclinical models of multiple myeloma results in a robust prevention of bone loss and preservation of bone strength, without apparent effects on tumor growth. These data raise the possibility of targeting sclerostin for the treatment of cancer patients with bone metastasis. Sclerostin is emerging as a valuable target to prevent the bone destruction that accompanies the growth of cancer cells in the bone. Further studies will focus on combining anti-sclerostin therapy with tumor-targeted agents to achieve both beneficial skeletal outcomes and inhibition of tumor progression.
Collapse
Affiliation(s)
- Michelle M McDonald
- The Garvan Institute of Medical Research, Sydney, Australia
- St. Vincent's School of Medicine, University of New South Wales, Sydney, Australia
| | - Jesus Delgado-Calle
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
- Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA.
| |
Collapse
|
|
41
|
Kogawa M, Khalid KA, Wijenayaka AR, Ormsby RT, Evdokiou A, Anderson PH, Findlay DM, Atkins GJ. Recombinant sclerostin antagonizes effects of ex vivo mechanical loading in trabecular bone and increases osteocyte lacunar size. Am J Physiol Cell Physiol 2017; 314:C53-C61. [PMID: 28978523 DOI: 10.1152/ajpcell.00175.2017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sclerostin has emerged as an important regulator of bone mass. We have shown that sclerostin can act by targeting late osteoblasts/osteocytes to inhibit bone mineralization and to upregulate osteocyte expression of catabolic factors, resulting in osteocytic osteolysis. Here we sought to examine the effect of exogenous sclerostin on osteocytes in trabecular bone mechanically loaded ex vivo. Bovine trabecular bone cores, with bone marrow removed, were inserted into individual chambers and subjected to daily episodes of dynamic loading. Cores were perfused with either osteogenic media alone or media containing human recombinant sclerostin (rhSCL) (50 ng/ml). Loaded control bone increased in apparent stiffness over time compared with unloaded bone, and this was abrogated in the presence of rhSCL. Loaded bone showed an increase in calcein uptake as a surrogate of mineral accretion, compared with unloaded bone, in which this was substantially inhibited by rhSCL treatment. Sclerostin treatment induced a significant increase in the ionized calcium concentration in the perfusate and the release of β-CTX at several time points, an increased mean osteocyte lacunar size, indicative of osteocytic osteolysis, and the expression of catabolism-related genes. Human primary osteocyte-like cultures treated with rhSCL also released β-CTX from their matrix. These results suggest that osteocytes contribute directly to bone mineral accretion, and to the mechanical properties of bone. Moreover, it appears that sclerostin, acting on osteocytes, can negate this effect by modulating the dimensions of the lacunocanalicular porosity and the composition of the periosteocyte matrix.
Collapse
Affiliation(s)
- M Kogawa
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - K A Khalid
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - A R Wijenayaka
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - R T Ormsby
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - A Evdokiou
- Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Woodville, South Australia, Australia
| | - P H Anderson
- School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, South Australia , Australia
| | - D M Findlay
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - G J Atkins
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| |
Collapse
|
|
42
|
Zarei A, Hulley PA, Sabokbar A, Javaid MK. Co-expression of DKK-1 and Sclerostin in Subchondral Bone of the Proximal Femoral Heads from Osteoarthritic Hips. Calcif Tissue Int 2017; 100:609-618. [PMID: 28275825 PMCID: PMC5409924 DOI: 10.1007/s00223-017-0246-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 01/30/2017] [Indexed: 12/03/2022]
Abstract
BACKGROUND Osteoarthritis (OA) is a progressively degenerative joint disease influenced by structural and metabolic factors. There is growing evidence that subchondral bone is involved in both symptomatic and structural progression in OA. The Wnt pathway has been implicated in the progression of OA but the expression and function of the Wnt inhibitors, Dikkopf (DKK-1) and sclerostin (SOST), are unclear. METHODS We examined the regional distribution of DKK-1 and SOST in subchondral bone of the femoral head using resection specimens following arthroplasty in patients presenting with end-stage OA. Cylindrical cores for immunohistochemistry were taken through midpoint of full thickness cartilage defect, partial cartilage defect, through base of osteophyte and through macroscopically normal cartilage. RESULTS Subchondral bone was thickest in cores taken from regions with full cartilage defect and thinnest in cores taken from osteophyte regions. In subchondral bone, expression of both DKK-1 and SOST was observed exclusively in osteocytes. Expression was highest in subchondral bone in cores taken from regions with partial but not full thickness cartilage defects. DKK-1 but not SOST was expressed by chondrocytes in cores with macroscopically normal cartilage. CONCLUSION The current study describes the regional cellular distribution of SOST and DKK-1 in hip OA. Expression was highest in the osteocytes in bone underlying partial thickness cartilage defects. It is however not clear if this is a cause or a consequence of alterations in the overlying cartilage. However, it is suggestive of an active remodeling process which might be targeted by disease-modifying agents.
Collapse
Affiliation(s)
- Allahdad Zarei
- Botnar Research Centre, Nuffield Department of Orthopaedics, NDORMS, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Philippa A Hulley
- Botnar Research Centre, Nuffield Department of Orthopaedics, NDORMS, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Afsie Sabokbar
- Botnar Research Centre, Nuffield Department of Orthopaedics, NDORMS, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - M Kassim Javaid
- Botnar Research Centre, Nuffield Department of Orthopaedics, NDORMS, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Oxford, OX3 7LD, UK.
| |
Collapse
|
|
43
|
Guo W, Pencina KM, O'Connell K, Montano M, Peng L, Westmoreland S, Glowacki J, Bhasin S. Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss. Bone 2017; 97:209-215. [PMID: 28132908 PMCID: PMC5985824 DOI: 10.1016/j.bone.2017.01.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 01/07/2017] [Accepted: 01/25/2017] [Indexed: 11/30/2022]
Abstract
UNLABELLED HIV-infected individuals are at an increased risk of osteoporosis despite effective viral suppression. Observations that myostatin null mice have increased bone mass led us to hypothesize that simian immunodeficiency virus (SIV)-associated bone loss may be attenuated by blocking myostatin/TGFβ signaling. In this proof-of-concept study, pair-housed juvenile male rhesus macaques were inoculated with SIVmac239. Four weeks later, animals were treated with vehicle or Fc-conjugated soluble activin receptor IIB (ActR2B·Fc, iv. 10mg∗kg-1∗week-1) - an antagonist of myostatin and related members of TGFβ superfamily. Limb and trunk bone mineral content (BMC) and density (BMD) using dual-energy X-Ray absorptiometry, circulating markers of bone growth and turnover, and serum testosterone levels were measured at baseline and during the 12-week intervention period. The increase in BMC was significantly greater in the ActRIIB.Fc-treated group (+8g) than in the placebo group (-4g) (p<0.05). BMD also increased significantly more in the ActRIIB.Fc-treated macaques (+0.03g/cm2) than in the placebo-treated animals (+0g/cm2) (p<0.005). Serum osteocalcin was about two-fold higher in the ActRIIB.Fc-treated group than in the placebo group (p<0.05), but serum C-terminal telopeptide and testosterone levels did not differ significantly between groups. The expression levels of TNFalpha (p<0.05), GADD45 (p<0.005), and sclerostin (p<0.038) in the bone-marrow were significantly lower in the ActRIIB.Fc-treated group than in the placebo group. CONCLUSION The administration of ActRIIB.FC in SIV-infected juvenile macaques significantly increases BMC and BMD in association with reduced expression levels of markers of bone marrow inflammation.
Collapse
Affiliation(s)
- Wen Guo
- Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
| | - Karol M Pencina
- Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Karyn O'Connell
- Department of Comparative Pathology, New England Primate Research Center, One Pine Hill Drive, PO Box 9102, Southborough, MA 01772-9102, United States
| | - Monty Montano
- Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Liming Peng
- Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Susan Westmoreland
- Department of Comparative Pathology, New England Primate Research Center, One Pine Hill Drive, PO Box 9102, Southborough, MA 01772-9102, United States
| | - Julie Glowacki
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Shalender Bhasin
- Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| |
Collapse
|
|
44
|
Weivoda MM, Youssef SJ, Oursler MJ. Sclerostin expression and functions beyond the osteocyte. Bone 2017; 96:45-50. [PMID: 27888056 PMCID: PMC5328839 DOI: 10.1016/j.bone.2016.11.024] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 11/17/2016] [Accepted: 11/21/2016] [Indexed: 11/24/2022]
Abstract
Sclerostin, the product of the SOST gene, is a secreted inhibitor of Wnt signaling that is produced by osteocytes to regulate bone formation. While it is often considered an osteocyte-specific protein, SOST expression has been reported in numerous other cell types, including hypertrophic chondrocytes and cementocytes. Of interest, SOST/sclerostin expression is altered in certain pathogenic conditions, including osteoarthritis and rheumatic joint disease, and it is unclear whether sclerostin plays a protective role or whether sclerostin may mediate disease pathogenesis. Therefore, as anti-sclerostin antibodies are being developed for the treatment of osteoporosis, it is important to understand the functions of sclerostin beyond the regulation of bone formation.
Collapse
Affiliation(s)
- Megan M Weivoda
- Division of Endocrinology, Metabolism, Nutrition & Diabetes, Mayo Clinic, USA.
| | - Stephanie J Youssef
- Division of Endocrinology, Metabolism, Nutrition & Diabetes, Mayo Clinic, USA
| | - Merry Jo Oursler
- Division of Endocrinology, Metabolism, Nutrition & Diabetes, Mayo Clinic, USA
| |
Collapse
|
|
45
|
Delgado-Calle J, Sato AY, Bellido T. Role and mechanism of action of sclerostin in bone. Bone 2017; 96:29-37. [PMID: 27742498 PMCID: PMC5328835 DOI: 10.1016/j.bone.2016.10.007] [Citation(s) in RCA: 308] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Revised: 08/29/2016] [Accepted: 10/10/2016] [Indexed: 12/14/2022]
Abstract
After discovering that lack of Sost/sclerostin expression is the cause of the high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive animal experimentation and clinical studies demonstrated that sclerostin plays a critical role in bone homeostasis and that its deficiency or pharmacological neutralization increases bone formation. Dysregulation of sclerostin expression also underlies the pathophysiology of skeletal disorders characterized by loss of bone mass, as well as the damaging effects of some cancers in bone. Thus, sclerostin has quickly become a promising molecular target for the treatment of osteoporosis and other skeletal diseases, and beneficial skeletal outcomes are observed in animal studies and clinical trials using neutralizing antibodies against sclerostin. However, the anabolic effect of blocking sclerostin decreases with time, bone mass accrual is also accompanied by anti-catabolic effects, and there is bone loss over time after therapy discontinuation. Further, the cellular source of sclerostin in the bone/bone marrow microenvironment under physiological and pathological conditions, the pathways that regulate sclerostin expression and the mechanisms by which sclerostin modulates the activity of osteocytes, osteoblasts, and osteoclasts remain unclear. In this review, we highlight the current knowledge on the regulation of Sost/sclerotin expression and its mechanism(s) of action, discuss novel observations regarding its role in signaling pathways activated by hormones and mechanical stimuli in bone, and propose future research needed to understand the full potential of therapeutic interventions that modulate Sost/sclerostin expression.
Collapse
Affiliation(s)
- Jesus Delgado-Calle
- Department of Anatomy and Cell Biology, Indianapolis, IN, United States; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States.
| | - Amy Y Sato
- Department of Anatomy and Cell Biology, Indianapolis, IN, United States.
| | - Teresita Bellido
- Department of Anatomy and Cell Biology, Indianapolis, IN, United States; Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, United States; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States.
| |
Collapse
|
|
46
|
Sebastian A, Loots GG. Transcriptional control of Sost in bone. Bone 2017; 96:76-84. [PMID: 27771382 DOI: 10.1016/j.bone.2016.10.009] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 09/15/2016] [Accepted: 10/10/2016] [Indexed: 01/07/2023]
Abstract
Sclerostin is an osteocyte derived negative regulator of bone formation. A highly specific expression pattern and the exclusive bone phenotype have made Sclerostin an attractive target for therapeutic intervention in treating metabolic bone diseases such as osteoporosis and in facilitating fracture repair. Understanding the molecular mechanisms that regulate Sclerostin transcription is of great interest as it may unveil new avenues for therapeutic approaches. Such studies may also elucidate how various signaling pathways intersect to modulate bone metabolism. Here we review the current understanding of the upstream molecular mechanisms that regulate Sost/SOST transcription, in bone.
Collapse
Affiliation(s)
- Aimy Sebastian
- Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA
| | - Gabriela G Loots
- Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA.
| |
Collapse
|
|
47
|
Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Phatharacharukul P, Ungprasert P. Hepatitis C virus infection and risk of osteoporosis: A meta-analysis. Saudi J Gastroenterol 2017; 23:216-221. [PMID: 28721974 PMCID: PMC5539674 DOI: 10.4103/sjg.sjg_452_16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Hepatitis C virus (HCV) infection is one of the most common infections worldwide. Several epidemiologic studies have suggested that patients with HCV infection might be at an increased risk of osteoporosis. However, the data on this relationship remains inconclusive. This meta-analysis was conducted with the aim to summarize all available evidence. MATERIALS AND METHODS A literature search was performed using MEDLINE and EMBASE databases from inception to June 2016. Studies that reported relative risks, odd ratios (OR), or hazard ratios comparing the risk of osteoporosis among HCV-infected patients versus those without HCV infection were included. Pooled OR and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS Four studies met our eligibility criteria and were included in the analysis. We found a higher risk of osteoporosis among patients with chronic HCV with OR of 1.65 (95% CI: 0.98-2.77). Sensitivity analysis including only studies with higher quality yielded a higher OR, and the result was statistically significant (OR: 2.47; 95% CI: 1.03-5.93). CONCLUSIONS Our study demonstrated a higher risk of osteoporosis among HCV-infected patients. Further studies are required to clarify how this risk should be addressed in clinical practice.
Collapse
Affiliation(s)
- Karn Wijarnpreecha
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, New York, USA,Address for correspondence: Dr. Karn Wijarnpreecha, Department of Internal Medicine, Bassett Medical Center, Cooperstown, New York, USA. E-mail:
| | - Charat Thongprayoon
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, New York, USA
| | | | | | - Patompong Ungprasert
- Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA,Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
48
|
Robling AG, Kang KS, Bullock WA, Foster WH, Murugesh D, Loots GG, Genetos DC. Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation. Bone 2016; 92:180-188. [PMID: 27601226 PMCID: PMC6673653 DOI: 10.1016/j.bone.2016.09.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 08/29/2016] [Accepted: 09/02/2016] [Indexed: 11/17/2022]
Abstract
Sclerostin (Sost) is a negative regulator of bone formation that acts upon the Wnt signaling pathway. Sost is mechanically regulated at both mRNA and protein level such that loading represses and unloading enhances Sost expression, in osteocytes and in circulation. The non-coding evolutionarily conserved enhancer ECR5 has been previously reported as a transcriptional regulatory element required for modulating Sost expression in osteocytes. Here we explored the mechanisms by which ECR5, or several other putative transcriptional enhancers regulate Sost expression, in response to mechanical stimulation. We found that in vivo ulna loading is equally osteoanabolic in wildtype and Sost-/- mice, although Sost is required for proper distribution of load-induced bone formation to regions of high strain. Using Luciferase reporters carrying the ECR5 non-coding enhancer and heterologous or homologous hSOST promoters, we found that ECR5 is mechanosensitive in vitro and that ECR5-driven Luciferase activity decreases in osteoblasts exposed to oscillatory fluid flow. Yet, ECR5-/- mice showed similar magnitude of load-induced bone formation and similar periosteal distribution of bone formation to high-strain regions compared to wildtype mice. Further, we found that in contrast to Sost-/- mice, which are resistant to disuse-induced bone loss, ECR5-/- mice lose bone upon unloading to a degree similar to wildtype control mice. ECR5 deletion did not abrogate positive effects of unloading on Sost, suggesting that additional transcriptional regulators and regulatory elements contribute to load-induced regulation of Sost.
Collapse
Affiliation(s)
- Alexander G Robling
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University/Purdue University at Indianapolis, Indianapolis, IN 46202, USA
| | - Kyung Shin Kang
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Whitney A Bullock
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - William H Foster
- Department of Anatomy, Physiology and Cell Biology, University of California Davis, Davis, CA, USA
| | - Deepa Murugesh
- Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Gabriela G Loots
- Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA; Molecular and Cell Biology Unit, School of Natural Sciences, University of California at Merced, Merced, CA, USA
| | - Damian C Genetos
- Department of Anatomy, Physiology and Cell Biology, University of California Davis, Davis, CA, USA.
| |
Collapse
|
|
49
|
Wijenayaka AR, Prideaux M, Yang D, Morris HA, Findlay DM, Anderson PH, Atkins GJ. Early response of the human SOST gene to stimulation by 1α,25-dihydroxyvitamin D 3. J Steroid Biochem Mol Biol 2016; 164:369-373. [PMID: 26690786 DOI: 10.1016/j.jsbmb.2015.12.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 11/24/2015] [Accepted: 12/07/2015] [Indexed: 11/30/2022]
Abstract
The osteocyte expressed gene SOST encodes sclerostin, a potent negative regulator of bone formation and inducer of bone resorption. We have recently demonstrated that the human SOST gene is positively regulated in response to 1α,25-dihydroxyvitamin D3 (1,25D). Responsiveness may be mediated at least in part by a single classical DR3-type vitamin D response element (VDRE). In this study we examined the early responsiveness of the SOST gene to both 1,25D and to parathyroid hormone (PTH), a known repressor of SOST expression, in SaOS2 cells differentiated to an osteocyte-like stage of cell maturation. Both SOST mRNA levels and sclerostin protein levels increased in these cultures as early as 3h post-treatment with 1,25D and declined in response to PTH in the same timeframe. For 1,25D, the level of induced SOST appeared dependent on the extent, to which the degradative enzyme 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1) was induced. Together with the observed rapid decrease in SOST/sclerostin levels in response to PTH, endocrine regulation of sclerostin production appears to be an important determinant of sclerostin levels. These findings confirm that the human SOST gene and sclerostin expression can be considered to be directly 1,25D-responsive in osteocytes.
Collapse
Affiliation(s)
- Asiri R Wijenayaka
- Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia.
| | - Matthew Prideaux
- Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia
| | - Dongqing Yang
- Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia
| | - Howard A Morris
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
| | - David M Findlay
- Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia
| | - Paul H Anderson
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
| | - Gerald J Atkins
- Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia
| |
Collapse
|
|
50
|
Baschant U, Henneicke H, Hofbauer LC, Rauner M. Sclerostin Blockade-A Dual Mode of Action After All? J Bone Miner Res 2016; 31:1787-1790. [PMID: 27597566 DOI: 10.1002/jbmr.2988] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 08/25/2016] [Accepted: 09/01/2016] [Indexed: 12/24/2022]
Affiliation(s)
- Ulrike Baschant
- Department of Medicine 3, Technische Universität Dresden, Dresden, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Holger Henneicke
- Department of Medicine 3, Technische Universität Dresden, Dresden, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.,Deutsche Forschungsgemeinschaft (DFG)-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine 3, Technische Universität Dresden, Dresden, Germany. .,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany. .,Deutsche Forschungsgemeinschaft (DFG)-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
| | - Martina Rauner
- Department of Medicine 3, Technische Universität Dresden, Dresden, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| |
Collapse
|