Connective Tissue Research最新文献

{"title":"Intermittent PTH induces cartilage healing after experimentally induced TMJ degeneration.","authors":"Eliane H Dutra, Po-Jung Chen, Christina D Casciani, Yueying Zhou, Sunil Wadhwa, Marja Hurley, Sumit Yadav","doi":"10.1080/03008207.2026.2737680","DOIUrl":"https://doi.org/10.1080/03008207.2026.2737680","url":null,"abstract":"<p><strong>Purpose: </strong>Our data suggest that intermittent parathyroid hormone administration (PTH) may exert chondrogenerative effects on the cartilage of the temporomandibular joint (TMJ), however, it is not known whether PTH could prevent/reverse TMJ degeneration. Our aim was to evaluate the role of PTH in an experimental mouse model of this condition.</p><p><strong>Methods: </strong>The triple collagen transgenic mice (Col1a1/Col3.6-tpz × Col2a1/Col2-cyan × Col10a1/Col10-mCherry) were used. Metal tubes were bonded to the incisors of 6-week-old male mice to induce an anterior crossbite and TMJ degeneration. The mice then received daily injections of PTH or saline solution (control groups) for 2 weeks.</p><p><strong>Results: </strong>We observed a substantial decrease in TMJ cartilage thickness in Degeneration Control mice compared to Control. However, mice receiving PTH injections presented with increased cartilage thickness and proteoglycan distribution compared to Degeneration Control. There was a decrease in Col1a1 and an increase in Col10a1 positive cells in the TMJ cartilage of Degeneration Control mice compared to Control group, effect reversed by PTH treatment. Additionally, we observed increased markers for osteoarthritis in Degeneration Control mice compared to control, but mice receiving PTH injections presented with increased chondrocyte proliferation and decreased degeneration markers.</p><p><strong>Conclusions: </strong>Intermittent PTH treatment following experimental TMJ degeneration increased cartilage thickness, proteoglycan distribution, and chondroprogenitor proliferation while reducing markers of osteoarthritis in TMJ cartilage.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-10"},"PeriodicalIF":1.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing of the meniscus: insights into cellular heterogeneity and therapeutic targets.","authors":"Xiaoyang Xu, Ningyi Guo, Kaiyue Diao, Bingbing Xu, Jianquan Wang","doi":"10.1080/03008207.2026.2739996","DOIUrl":"https://doi.org/10.1080/03008207.2026.2739996","url":null,"abstract":"<p><strong>Purpose: </strong>As a key component of the knee joint, meniscal health and function directly influence joint stability and the progression of degenerative conditions such as osteoarthritis. Single-cell RNA sequencing has been increasingly applied in meniscus research, providing new insights into tissue complexity and intercellular interactions. This review summarizes recent advances in single-cell RNA sequencing and its applications in meniscus research.</p><p><strong>Methods: </strong>Relevant literature was reviewed and synthesized, with a focus on cell type identification, subpopulation heterogeneity, disease pathogenesis, and potential therapeutic targets.</p><p><strong>Results: </strong>The findings indicate that single-cell RNA sequencing can elucidate the critical roles of specific meniscal cell clusters in maintaining tissue homeostasis, mediating degenerative processes, and facilitating injury repair, thereby providing a foundation for early diagnosis, targeted interventions, and tissue engineering strategies. Nevertheless, several challenges still hinder the clinical translation of single-cell RNA sequencing findings, including the dense extracellular matrix of the meniscus, difficulties in cell dissociation, limited cell viability and yield, cross-species differences, inconsistent analytical workflows, high sequencing costs, and the loss of spatial information.</p><p><strong>Conclusions: </strong>Integration of single-cell RNA sequencing with spatial transcriptomics, multi-omics approaches, and analyses of the meniscus and adjacent joint tissues may help identify disease-related biomarkers, support patient stratification, guide targeted interventions, and advance tissue engineering and regenerative medicine strategies for meniscus degeneration and osteoarthritis.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-16"},"PeriodicalIF":1.9,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Re-evaluating the role of IL-1Ra gene therapy in knee osteoarthritis: a case for autologous conditioned serum as a practical alternative.","authors":"Valtteri Peitso, Ron Ellis, Karman Ng, Mickael Hiligsmann, Jean-Yves Reginster, C Wayne McIlwraith, Ali Mobasheri","doi":"10.1080/03008207.2026.2736271","DOIUrl":"https://doi.org/10.1080/03008207.2026.2736271","url":null,"abstract":"<p><p>Osteoarthritis (OA) of the knee remains one of the most prevalent and disabling musculoskeletal conditions worldwide, with few disease-modifying options beyond joint replacement. The pro-inflammatory cytokine interleukin-1 (IL-1) has long been implicated in the pathogenesis of OA, and approaches to block IL-1 activity have included recombinant proteins, small molecules, autologous blood-derived biologics, and most recently, viral vector-based gene therapies delivering interleukin-1 receptor antagonist (IL-1Ra). Gene therapy platforms such as PCRX-201 (Pacira) and GNSC-001 (Genascence) represent a technical advance, aiming for durable intra-articular IL-1Ra expression from a single injection. However, these approaches are expensive, logistically complex, and face challenges of immune barriers to repeat dosing, cost of goods (COGS), and uncertain long-term safety, efficacy and cost-effectiveness.By contrast, autologous conditioned serum (ACS), marketed for human use as Orthokine (also Regenokine) and for veterinary use under trade names such as IRAP, IRAP ProEAS™, and IRAP II, delivers IL-1Ra directly to the joint using the patient's own blood. Though evidence is modest, ACS provides a mechanistically overlapping anti-inflammatory approach with lower cost, repeatability, and safety advantages. ACS is already clinically applied in Europe and in veterinary medicine in Europe and the U.S. whereas IL-1Ra gene therapy remains in mid-stage clinical trials. Until gene therapy demonstrates clear advantages in durability, disease modification, and cost-effectiveness, ACS may represent a more pragmatic and earlier option in the sequence of intra-articular treatments, ahead of where gene therapy would enter, in selected clinical contexts for targeting IL-1 in patients with knee OA.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-16"},"PeriodicalIF":1.9,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MST1 inhibition mitigates fat deposition in rotator cuff tears by modulating the WNT/β-catenin pathway.","authors":"Liang Bao, Bing Zhang, Xin Xue, Cong Liu, Tao Zhou","doi":"10.1080/03008207.2026.2731155","DOIUrl":"https://doi.org/10.1080/03008207.2026.2731155","url":null,"abstract":"<p><strong>Purpose: </strong>Fatty infiltration of the supraspinatus muscle following rotator cuff tear (RCT) is a major pathological factor leading to poor functional outcomes, yet effective treatments are lacking. The kinase mammalian Sterile 20-like kinase 1 (MST1) has been implicated in metabolic disorders, but its role in RCT-associated muscle steatosis remains unexplored.</p><p><strong>Methods: </strong>Using a murine RCT model, fatty infiltration was assessed via Oil Red O staining, triglyceride content, and expression of adipogenic markers. Fibro/adipogenic progenitors (FAPs) were isolated for in vitro mechanistic studies of MST1 on fatty infiltration. In vivo knockdown of MST1 was achieved via local lentiviral shRNA injection. Masson's trichrome staining and myogenic regulatory protein were used to evaluate muscle atrophy.</p><p><strong>Results: </strong>MST1 expression was upregulated in the supraspinatus muscle post-RCT, correlating with progressive lipid accumulation. MST1 knockdown in FAPs impaired adipogenic differentiation, reducing lipid droplets and the expression of PPARγ and FABP4. Mechanistically, MST1 depletion activated the WNT/β-catenin signaling pathway, and its inhibition reversed the anti-adipogenic effect. In vivo, MST1 knockdown attenuated fatty infiltration, suppressed the adipogenic program, and alleviated muscle atrophy in RCT mice.</p><p><strong>Conclusions: </strong>Our findings unveil a pivotal role for MST1 in driving fatty infiltration by regulating FAP adipogenesis via the WNT/β-catenin pathway. Targeted inhibition of MST1 represents a promising therapeutic strategy to mitigate muscle steatosis and alleviate muscle atrophy after RCT.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-11"},"PeriodicalIF":1.9,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rg3 attenuates osteoarthritis progression by modulating the Nrf2-mediated autophagy pathway.","authors":"Xinjian Lu, Zhaoyang Wang, Weifeng Hu, Jiong Hu, Yang Zou","doi":"10.1080/03008207.2026.2731109","DOIUrl":"https://doi.org/10.1080/03008207.2026.2731109","url":null,"abstract":"<p><strong>Purpose: </strong>Osteoarthritis (OA) is a chronic and progressive joint disorder characterized by persistent inflammation, extracellular matrix (ECM) disruption, and chondrocyte apoptosis. This study aimed to investigate the protective effects of ginsenoside Rg3 (Rg3), a natural steroidal saponin from <i>Panax ginseng</i>, on OA and to elucidate its underlying molecular mechanisms.</p><p><strong>Methods: </strong>The effects of Rg3 were evaluated using a combination of network pharmacology, molecular docking, and experimental validation in vitro and in vivo. IL-1β-stimulated chondrocytes and a mouse OA model induced by destabilization of the medial meniscus (DMM) served as experimental platforms. Inflammatory mediators, ECM-associated markers, and proteins related to apoptosis and autophagy were analyzed by qPCR, Western blot, immunofluorescence, and flow cytometry. Molecular docking was performed to predict potential targets and signaling pathways involved.</p><p><strong>Results: </strong>Rg3 significantly inhibited IL-1β-induced inflammation by downregulating iNOS, COX-2, and IL-6 expression. It alleviated ECM degradation through suppression of MMP-13 and ADAMTS-5 and preservation of collagen II and aggrecan. Rg3 reduced chondrocyte apoptosis via modulation of Bcl-2, Bax, and cleaved caspase-3, while enhancing autophagic activity by regulating LC3-II, ATG7, and Beclin1. Molecular docking and protein analyses indicated activation of the Nrf2/HO-1 pathway, implicating its role in the observed protective effects.</p><p><strong>Conclusions: </strong>Rg3 exerts therapeutic effects in OA by activating Nrf2/HO-1 signaling, promoting autophagy, inhibiting inflammation, and protecting cartilage from degeneration, highlighting its potential as a candidate for OA management.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-18"},"PeriodicalIF":1.9,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential expression of NEK7-NLRP3 inflammasome-related genes in systemic sclerosis dermal fibroblasts: a subtype-specific analysis.","authors":"Tuba Yuce Inel, Ufkay Karabay, Mehtap Yuksel Egrilmez, Fatih Alp Ozturk, Haluk Vayvada, Merih Birlik","doi":"10.1080/03008207.2026.2729289","DOIUrl":"https://doi.org/10.1080/03008207.2026.2729289","url":null,"abstract":"<p><strong>Purpose: </strong>This study investigated the expression of NEK7-NLRP3 inflammasome-related genes in dermal fibroblasts from patients with systemic sclerosis (SSc), focusing on limited (lSSc) and diffuse cutaneous (dSSc) subtypes and their association with skin fibrosis.</p><p><strong>Methods: </strong>Dermal fibroblasts were obtained from patients with SSc and age-matched healthy controls. Messenger RNA expression of NEK7, NLRP3, ASC, caspase-1, IL-1β, IL-18, and COL1A1 was measured by real-time polymerase chain reaction.</p><p><strong>Results: </strong>The cohort comprised 13 patients with SSc (mean age 53.8 ± 11.7 years, 69.2% female, 53.8% dSSc) and healthy controls. Modified Rodnan skin score (mRSS) and Medsger severity scores were significantly higher in dSSc than in lSSc (<i>p</i> < 0.05), and were strongly correlated (<i>r</i> = 0.893, <i>p</i> < 0.001). Overall expression of inflammasome-related genes did not differ significantly between the total SSc group and controls. However, subgroup analysis revealed a distinct molecular profile. NEK7 and IL-1β expression levels were significantly higher in lSSc fibroblasts than in dSSc fibroblasts (<i>p</i> = 0.01 and <i>p</i> = 0.015, respectively), while NLRP3 expression was increased in lSSc compared with controls (<i>p</i> = 0.01). Within the lSSc subgroup, IL-18 levels were inversely correlated with mRSS (<i>r</i> = -0.883, <i>p</i> = 0.020), and caspase-1 expression was negatively correlated with age (<i>r</i> = -0.928, <i>p</i> = 0.008).</p><p><strong>Conclusion: </strong>These findings identify a subtype-specific pattern of inflammasome-related gene expression in SSc dermal fibroblasts and suggest a potential association with the fibrotic phenotype. Further protein-level and functional studies are warranted.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-8"},"PeriodicalIF":1.9,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Fam83h</i> affected adhesion ability and extracellular matrix collagen formation in ameloblasts.","authors":"Mingmei Meng, Yongting Xie, Liyan Shi, Qizhao Ma, Jing Zou","doi":"10.1080/03008207.2026.2711131","DOIUrl":"10.1080/03008207.2026.2711131","url":null,"abstract":"<p><strong>Purpose: </strong>Amelogenesis imperfecta (AI) is a group of inherited diseases characterized by enamel defects. Mutation in multiple genes may cause AI. The objective of this study was to investigate the specific roles of Family with sequence similarity 83 member H (FAM83H) in AI and determine its effect on ameloblasts.</p><p><strong>Methods: </strong>To investigate the impact of Fam83h on ameloblast gene expression, we utilized ameloblast line HAT-7 cells with knockdown of Fam83h gene for transcriptome sequencing. The experimental cell samples were undergone library preparation and RNA sequencing expreiments. Cell Adhesion test kit was employed to evaluate the influence of Fam83h on HAT-7 cell adhesion ability. RT-qPCR and western blot were conducted to analyze the expression levels of integrin and collagen proteins upon downregulation of Fam83h.</p><p><strong>Results: </strong>RNA-seq analysis revealed differential expression of 572 genes in HAT-7 cells with knockdown of Fam83h gene, including 285 up-regulated genes and 287 down-regulated genes. GO and KEGG enrichment analysis indicated that Fam83h could modulate collagen synthesis in ameloblasts as well as affect the focal adhesion pathway. In the cell adhesion assay, we observed a decrease in adhesion ability due to downregulation of Fam83h in HAT-7 cell line. Furthermore, it was found that Fam83h can upregulated extracellular matrix collagen formation in ameloblasts.</p><p><strong>Conclusions: </strong><i>Fam83h</i> may affect the adhesion ability and extracellular matrix collagen formation in ameloblasts, leading to AI.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"539-549"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence of walking speed on the mechanoresponsiveness of biomarkers.","authors":"Amy L McNulty, Karl N Thomas, Betty Liu, Sophia Y Kim-Wang, Zoë A Englander, James A Coppock, Kwadwo Owusu-Akyaw, Andrzej S Kosinski, Louis E DeFrate","doi":"10.1080/03008207.2026.2725705","DOIUrl":"10.1080/03008207.2026.2725705","url":null,"abstract":"<p><strong>Purpose: </strong>The goal of this study was to examine short-term biomarker responses to walking at three different speeds in healthy individuals.</p><p><strong>Methods: </strong>Healthy participants completed three study visits. At each visit, participants rested supine for 45 minutes, after which blood was collected. Next, participants completed a 30-minute treadmill walk, and another blood sample was collected. Finally, participants rested in a supine position for 45 minutes, after which a third blood sample was collected. At each visit, the treadmill speed was varied so that participants walked at a slow, moderate, or brisk speed. Serum biomarker levels were measured for cartilage oligomeric matrix protein (COMP), matrix metalloproteinase-3 (MMP-3), interleukin-6 (IL-6), and lubricin (PRG4).</p><p><strong>Results: </strong>Both COMP (<i>p</i> < 0.0001) and MMP-3 (<i>p</i> < 0.0005) showed significant increases in serum levels between pre- and post-activity measurements. The concentrations of both COMP (<i>p</i> < 0.0001) and MMP-3 (<i>p</i> = 0.04) decreased significantly from the post-activity to the recovery timepoint. Increasing walking speed elicited an increase in both serum COMP and MMP-3 concentrations (<i>p</i> < 0.05). On the other hand, we did not detect alterations in serum IL-6 or PRG4 concentrations due to walking or recovery.</p><p><strong>Conclusions: </strong>Given the relationship we found between biomarker levels and walking speed, COMP and MMP-3 may be biomarkers reflective of the cartilage response to mechanical loading. Furthermore, these data suggest that mechanical loading through exercise may be a means to detect aberrant mechanical response. Finally, these findings serve as important baseline data for future studies investigating biomarker levels in those at risk for OA.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"608-615"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium phosphate nanoparticles carrying YAP plasmid promote osteogenic potential in dental pulp stem cells by modulating BMP-2 expression and macrophage M2-like phenotype.","authors":"Yingjie Xu, Fanwen Meng","doi":"10.1080/03008207.2026.2726456","DOIUrl":"10.1080/03008207.2026.2726456","url":null,"abstract":"<p><strong>Purpose: </strong>YAP is a well-established regulator of both osteogenic differentiation and macrophage polarization; however, conventional transfection reagents such as Lipofectamine are limited by inherent cytotoxicity. Herein, we investigated the efficacy of PEI-modified calcium phosphate nanoparticles (CaP/PEI-YAP) in enhancing DPSC osteogenic potential and elucidated the underlying macrophage-mediated mechanisms.</p><p><strong>Methods: </strong>We synthesized and characterized CaP/PEI-YAP by XRD, FTIR, TEM, and particle size potentiostat, followed by assessing their uptake efficiency and cytotoxicity in DPSCs. The effect of CaP/PEI-YAP on osteoblastic differentiation and migration of DPSCs were evaluated. Extracellular calcium deposition was examined by Alizarin Red staining. Besides, we explored the impact of CaP/PEI-YAP on macrophage polarization.</p><p><strong>Results: </strong>CaP/PEI-YAP could be taken up by DPSCs and exhibited lower cytotoxicity compared to lipofectamine 2000. DPSCs viability was decreased when exposed to the synthesized CaP/PEI-YAP (100 μg/mL). Compared with the CaP/PEI without YAP expression plasmid, cell migration of DPSCs in the CaP/PEI-YAP group was significantly elevated at 24 and 48 h, as demonstrated by wound healing and transwell assays. Increases of ALP activity and Alizarin red staining intensity indicated that DPSCs had differentiated toward an osteogenic lineage and showed extracellular calcium deposition after uptake of CaP/PEI-YAP by DPSCs. CaP/PEI-YAP promoted macrophage M2-like phenotype with increased Arg-1 and BMP-2 while decreased iNOS expression.</p><p><strong>Conclusion: </strong>CaP/PEI-YAP constitute an innovative and promising instrument for targeted dental pulp regeneration, with mechanisms potentially involving the osteogenic potential of DPSCs and polarization of macrophages M2-like phenotype.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"616-627"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RARRES2 deficiency inhibits postmenopausal osteoporosis by promoting ferroptosis-mediated osteoclast differentiation via Nrf2/GPX4 axis inhibition.","authors":"Yifan Wang, Jiabin Lin, Xinyao Cui, Xinghan Zhao, Ziang Zheng, Haidong Liang, Wenji Song","doi":"10.1080/03008207.2026.2710162","DOIUrl":"10.1080/03008207.2026.2710162","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to investigate the effects of retinoic acid receptor responder 2 (RARRES2) on osteoclast differentiation in postmenopausal osteoporosis (PMOP) and to elucidate the underlying mechanisms.</p><p><strong>Methods: </strong>A rat model of PMOP was induced by bilateral ovariectomy (OVX) method, and an in vitro osteoclast differentiation model was induced by treating RAW264.7 cells with nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Femoral bone structure, biomechanical properties, histology, osteoclast activity, co‑localization of RARRES2/CMKLR1 with TRAP+ osteoclasts and Perilipin‑1+ bone marrow adipocytes, gene expression, Fe2+ levels, reactive oxygen species (ROS) level, and lipid peroxidation level were detected.</p><p><strong>Results: </strong>OVX model rats exhibited significant trabecular bone loss, compromised bone biomechanical properties, increased osteoclast numbers, elevated osteoclast differentiation markers, and upregulated RARRES2 expression compared with Sham controls. Co‑localization immunofluorescence revealed that RARRES2 was predominantly co‑localized with TRAP+ osteoclasts and Perilipin‑1+ bone marrow adipocytes. In vitro, RARRES2 knockdown markedly suppressed osteoclast differentiation, as evidenced by decreased osteoclast-related markers (NFATc1, CTSK, c-Fos, and F-actin) and reduced TRAP activity. Mechanistically, RARRES2 knockdown increased ferroptosis in osteoclasts, manifesting by decreased Nrf2, GPX4, HO-1, NQO1, and FTH1, along with increased ACSL4, Fe²⁺ accumulation , ROS production, and lipid peroxidation. These findings were also confirmed <i>in vivo</i>. Activation of Nrf2 with DMF partially reversed the ferroptotic alterations and osteoclast‑inhibiting effects induced by RARRES2 knockdown both <i>in vitro</i> and <i>in vivo</i>.</p><p><strong>Conclusion: </strong>RARRES2 knockdown inhibits osteoclast differentiation and alleviates PMOP progression by suppressing the activation of Nrf2/GPX4 and promoting osteoclast ferroptosis.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"509-523"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}