Journal of Orthopaedic Translation最新文献

{"title":"Combining polydioxanone-based scaffold and allogeneic adipose-derived mesenchymal stem cells enhances articular cartilage repair - a pre-clinical study","authors":"Emanuel Vitor Appolonio, Vittoria Guerra Altheman, Fernanda de Castro Stievanni, Gustavo dos Santos Rosa, Fernanda Barthelson Carvalho de Moura, Natalia Camargo Faraldo, Carlos Eduardo Fonseca Alves, Camila C. Kaleka, Pedro Debieux, Moises Cohen, Ana Liz Garcia Alves","doi":"10.1016/j.jot.2026.101193","DOIUrl":"10.1016/j.jot.2026.101193","url":null,"abstract":"<div><h3>Introduction</h3><div>Articular cartilage exhibits limited intrinsic regenerative capacity, making its repair a persistent clinical challenge. Polydioxanone (PDO) scaffolds offer biocompatibility, tunable degradation, and structural support, whereas adipose-derived mesenchymal stem cells (AD-MSCs) possess chondrogenic, immunomodulatory, and regenerative potential. This study evaluated the biocompatibility of the PDO scaffold <em>(Plenum Tissue Ortho)</em> and investigated its effectiveness in enhancing articular cartilage repair when combined with microfracture (MF) or allogeneic ovine adipose-derived mesenchymal stem cells (SadMSCs), in comparison with a collagen scaffold (COL), in a preclinical ovine model.</div></div><div><h3>Methods</h3><div>Twenty-four adult sheep were randomly allocated into six groups. Full-thickness chondral defects were created in the weight-bearing region of the medial femoral condyle and treated according to each group: Control (no treatment), MF alone, MF/COL, MF/PDO, SadMSC/COL, or SadMSC/PDO. SadMSCs were isolated, expanded, and characterized for viability, immunophenotyping, and trilineage differentiation. The biocompatibility of the PDO scaffold was assessed by cell adhesion and proliferation using Live/Dead staining and scanning electron microscopy. After 26 weeks, articular cartilage repair was evaluated macroscopically following ICRS scoring guidelines, histologically using the modified O'Driscoll score, and immunohistochemically for COL I, COL II, COL X, TGF-β2, and TGF-β3.</div></div><div><h3>Results</h3><div>PDO scaffolds supported the survival, adhesion, and proliferation of SadMSCs. Clinically, animals showed good recovery without major complications. At necropsy, no residual membranes, inflammation, or adverse reactions were detected. Macroscopically, the PDO/MF group presented the best repair scores, significantly superior to the Control, MF alone, MF/COL, SadMSC/COL, and SadMSC/PDO groups. Microscopically, SadMSC/PDO achieved the highest O'Driscoll and immunohistochemistry scores, with strong expression of COL II and TGF-β, along with reduced COL I and COL X, indicating hyaline-like cartilage formation. Multivariate analysis confirmed a strong positive correlation between COL II, TGF-β expression, and histological scores.</div></div><div><h3>Conclusion</h3><div>PDO scaffolds demonstrated excellent biocompatibility and, when combined with SadMSCs, promoted superior cartilage repair compared with COL scaffolds or MF alone. While PDO/MF achieved the best macroscopic outcomes, SadMSC/PDO provided the most favorable microscopic and molecular findings, suggesting that allogeneic AdMSCs seeded on PDO scaffolds enhance hyaline-like cartilage formation. These results highlight PDO and AD-MSC-based constructs as a promising alternative for translational strategies in cartilage repair.</div></div><div><h3>The translational potential of this article</h3><div>This study demonstrated that the combination of ","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"60 ","pages":"Article 101193"},"PeriodicalIF":9.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148854621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical evaluation of a fully threaded biodegradable magnesium alloy headless compression screw for enhanced fixation in small bones","authors":"Hiroshi Noguchi,&nbsp;Kotaro Hanada,&nbsp;Ryunosuke Watanabe,&nbsp;Yasukazu Totoki,&nbsp;Yohei Tomaru,&nbsp;Akira Ikumi,&nbsp;Akira Kitagawa,&nbsp;Sakiko Orui,&nbsp;Lulu Zhang,&nbsp;Hajime Mishima","doi":"10.1016/j.jot.2026.101201","DOIUrl":"10.1016/j.jot.2026.101201","url":null,"abstract":"<div><h3>Background</h3><div>Biodegradable magnesium (Mg) alloys have attracted attention as alternatives to conventional metallic implants; however, their clinical applicability to fully threaded headless compression (HC) screws has been scarcely investigated.</div></div><div><h3>Methods</h3><div>In this study, a fully threaded biodegradable Mg alloy HC screw was developed, and its mechanical performance, biological safety, and in vivo degradation behavior were systematically evaluated. Mechanical properties were assessed according to ASTM standards and compared with clinically used titanium (Ti) alloy and poly-L-lactic acid/hydroxyapatite (PLLA/HA) screws. Biological safety was evaluated in accordance with ISO 10993 and in compliance with Good Laboratory Practice. In vivo degradation behavior was investigated using a rabbit distal femoral condyle model.</div></div><div><h3>Results</h3><div>The Mg alloy HC screw demonstrated superior torsional strength compared with PLLA/HA screws and comparable insertion performance, along with enhanced fixation strength, compared with Ti alloy screws. No cytotoxicity, sensitization, or intracutaneous reactivity was observed. Although transient gas cavity formation was observed during the early implantation period, it progressively diminished over time and did not adversely affect bone formation or implant stability.</div></div><div><h3>Conclusion</h3><div>These findings indicate that the developed Mg alloy HC screw exhibits favorable mechanical performance, biocompatibility, and in vivo degradation. This study provides preclinical evidence supporting its potential clinical translation, particularly in eliminating the need for secondary implant removal surgery.</div></div><div><h3>The translational potential of this article</h3><div>This article focuses on the preclinical evaluation of a fully threaded Mg-alloy HC screw developed to improve fixation performance for small bone fractures. The results of this study have significant clinical potential for the fully threaded design of biodegradable Mg alloy implants in fracture treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"60 ","pages":"Article 101201"},"PeriodicalIF":9.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148854622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional ultrafast hydrogel for arthroscopic surgery: An enzymatically cross-linked, nanosilicate-reinforced system promotes dual cartilage and subchondral bone regeneration","authors":"Qiang Lian,&nbsp;Jianqun Wu,&nbsp;Yun Lian,&nbsp;Danfeng Du,&nbsp;Yangyi Yu,&nbsp;Yuanhao Fan,&nbsp;Shenlei Feng,&nbsp;Hang Zhou,&nbsp;Jiawei Li,&nbsp;Chengheng You,&nbsp;Ying Wang,&nbsp;Decheng Wu,&nbsp;Chao Liu,&nbsp;Guangheng Li","doi":"10.1016/j.jot.2026.101104","DOIUrl":"10.1016/j.jot.2026.101104","url":null,"abstract":"<div><h3>Background</h3><div>Arthroscopic repair of osteochondral (OC) defects using injectable hydrogels remains highly challenging due to the high-pressure, water-filled environment of the joint during arthroscopic surgery. Conventional hydrogels exhibit slow gelation kinetics, prolonged setting times, poor adhesion to wet tissues, and insufficient mechanical strength, rendering them prone to washout throughout the procedure.</div></div><div><h3>Methods</h3><div>To address these limitations, we incorporated a small amount of transglutaminase (TG) and synthetic lithium silicate nanoplatelets (SN) into a gelatin–oxidized starch (GelS) precursor and evaluated the regenerative performance of the resulting hydrogel under simulated arthroscopic conditions. In vivo, the hydrogels were implanted into osteochondral defects in rats to assess their repair efficacy.</div></div><div><h3>Results</h3><div>The GelS-TG-SN hydrogel demonstrated ultrafast enzymatic gelation, robust underwater adhesion, and significantly enhanced mechanical strength. It was cytocompatible, displayed anti-inflammatory activity, and supported context-dependent dual-lineage differentiation of Synovial-derived stem cells (SDSCs) chondrogenesis in a cartilage-like niche and PI3K–Akt–mediated osteogenesis in a vascular-like niche. Following 8-week implantation, it enabled coordinated regeneration of cartilage and subchondral bone, recapitulating native osteochondral architecture.</div></div><div><h3>Conclusion</h3><div>The GelS-TG-SN nanocomposite hydrogel offers a compelling strategy for effective osteochondral regeneration in arthroscopic surgical environments.</div></div><div><h3>The Translational Potential of this Article</h3><div>This hydrogel platform offers an elegant and clinically accessible solution for arthroscopic osteochondral repair. Its ultrafast gelation—achieved in under one minute—combined with resilient adhesion under constant irrigation enables seamless intraoperative application without auxiliary instrumentation. By capitalizing on the body's intrinsic osteochondral gradient, a single injection orchestrates synchronized regeneration of cartilage and subchondral bone. Such integration of procedural simplicity with inherent regenerative bioactivity underscores its promise as a genuinely “one-step” therapy ready for clinical translation.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101104"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GFRα2 identified in TBI-induced bone healing is a novel therapeutic target for osteoporosis via osteogenesis and angiogenesis","authors":"Huibo Ti,&nbsp;Zhenyu Zhang,&nbsp;Huaxin Kang,&nbsp;Yuechun Chen,&nbsp;Keyue Zhang,&nbsp;Shuwen Shi,&nbsp;Xian Wu,&nbsp;Zixin Luo,&nbsp;Xingchen Yao,&nbsp;Xielin Yan,&nbsp;Junjie Wu,&nbsp;Zhengdong Yuan,&nbsp;Hao Nie,&nbsp;Feng-lai Yuan,&nbsp;Xia Li","doi":"10.1016/j.jot.2026.101146","DOIUrl":"10.1016/j.jot.2026.101146","url":null,"abstract":"<div><h3>Background</h3><div>Osteoporosis (OP) is a systemic disease featured by reduced bone mass, deteriorated microstructure and elevated fracture risk. Traditional therapies mainly target direct regulators of bone remodeling. Emerging evidence suggests a critical crosstalk between the skeletal and nervous systems. Traumatic brain injury (TBI) markedly accelerates fracture healing, which holds great potential for OP treatment, yet the underlying mechanism remains unclear.</div></div><div><h3>Methods</h3><div>A mouse TBI plus femoral fracture model was established. Micro-CT, histomorphometry and transcriptome sequencing were performed. In vitro studies included qPCR, Western blot, ALP/Alizarin Red staining, co-culture, ELISA and tube formation assays. Ovariectomized (OVX) mice received tail vein injection of Gfrα2 overexpression plasmid or siRNA for in vivo validation.</div></div><div><h3>Results</h3><div>TBI significantly accelerated fracture healing with elevated GFRα2 in callus BMSCs. GFRα2 promoted BMSC osteogenesis by maintaining iron homeostasis via Ferritin Heavy Chain 1 (FTH1) and enhanced angiogenesis by increasing VEGFD secretion. In OVX mice, GFRα2 overexpression markedly improved bone mineral density, trabecular microstructure, bone formation rate and intraosseous angiogenesis.</div></div><div><h3>Conclusions</h3><div>GFRα2 serves as a key hub linking TBI to accelerated bone formation via dual effects on osteogenesis and angiogenesis. Targeting GFRα2 represents a promising therapeutic strategy against osteoporosis.</div></div><div><h3>The translational potential of this article</h3><div>This study identifis GFRα2 as a key mediator linking traumatic brain injury-accelerated bone formation to osteogenesis and angiogenesis. Targeting GFRα2 effectively ameliorates bone loss in osteoporotic mice by restoring both bone formation and intraosseous vascularization. These findings establish a novel neuro-osteogenic regulatory axis and provide a promising molecular target for developing new therapeutic strategies to treat osteoporosis and improve fracture healing in clinical practice.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101146"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging mechanisms and translational advances in musculoskeletal diseases","authors":"Tingting Xia,&nbsp;Bin Li","doi":"10.1016/j.jot.2026.101199","DOIUrl":"10.1016/j.jot.2026.101199","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101199"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148843032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to ‘Deer antler polypeptides promote osteogenesis for fracture healing via activating neurosensory PGE2/EP4/p-CREB axis’ [J Orthop Translat 58 (2026) 1–15/101112]","authors":"Yunfan He,&nbsp;Jihao Xi,&nbsp;Haoqiang Dai,&nbsp;Liang Fang,&nbsp;Yihe Yu,&nbsp;Yonggan Ying,&nbsp;Jin Li,&nbsp;Danqing Fu,&nbsp;Chenjie Xia","doi":"10.1016/j.jot.2026.101162","DOIUrl":"10.1016/j.jot.2026.101162","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101162"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13316171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author's reply to the Letters regarding ‘Selecting between UKA and HTO in the grey zone’","authors":"Jianbin Guo,&nbsp;Zhibo Liu,&nbsp;Yong Ding","doi":"10.1016/j.jot.2026.101136","DOIUrl":"10.1016/j.jot.2026.101136","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101136"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148843031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effect of mitochondrial transfer on bone tissue diseases: treatment strategy of mitochondrial transplantation and delivery technology","authors":"Zuping Wu,&nbsp;Yuzhe Guan,&nbsp;Ruifeng Song,&nbsp;Peng Chen,&nbsp;Xinyi Fang,&nbsp;Qian chen,&nbsp;Xiaoyan Chen","doi":"10.1016/j.jot.2026.101143","DOIUrl":"10.1016/j.jot.2026.101143","url":null,"abstract":"<div><div>Disruptions in bone tissue metabolic balance can lead to osteoporosis, osteoarthritis, rheumatoid arthritis, and bone tumors. This disruption typically manifests as reduced or abnormal bone mass, accompanied by pathological changes such as inflammation, fractures, and pain. Recent studies have revealed that mitochondrial dysfunction is prevalent in the aforementioned pathological processes, participating in the regulation of bone tissue cell function and intracellular immune function. Mitochondrial transfer, a newly discovered physiological phenomenon in recent years, can regulate mitochondrial function within recipient cells, thereby influencing metabolic activities, proliferation, differentiation, apoptosis, and immune function of various bone tissue cells. This article primarily reviews the regulatory effects of mitochondrial transfer associated with MSCs on various cells in bone and joint tissues. Given the role of mitochondrial transfer in regulating bone metabolism, we elucidate the application of mitochondrial transfer therapy in the treatment of osteoporosis, osteoarthritis, rheumatoid arthritis, and other bone tissue diseases.</div><div>The Translational Potential of this Article: This review elaborates in detail on the therapeutic strategies provided by mitochondrial transplantation technology or targeted mitochondrial delivery systems for the treatment of bone tissue diseases, based on the occurrence of mitochondrial transfer in bone tissue tips and its therapeutic effects on related diseases such as OA, RA, osteoporosis.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101143"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13314807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide alleviates osteoarthritis independent of weight loss via GLP-1R–mediated activation of autophagy through AKT/mTOR inhibition","authors":"Junming Lin,&nbsp;Mengliang Luo,&nbsp;Huaxin Tang,&nbsp;Kaifeng Lu,&nbsp;Yuexi Mou,&nbsp;Qilong Jiang,&nbsp;Xiaojun Yuan,&nbsp;Zhongliang Deng,&nbsp;Wenhua Xu,&nbsp;Mao Nie,&nbsp;Xianding Sun","doi":"10.1016/j.jot.2026.101166","DOIUrl":"10.1016/j.jot.2026.101166","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;&lt;strong&gt;Objective&lt;/strong&gt;&lt;/h3&gt;&lt;div&gt;The development of osteoarthritis (OA) is closely associated with systemic metabolic disorders, yet there remains a lack of disease-modifying therapeutic strategies that simultaneously target metabolic abnormalities and inflammatory responses. This study aims to systematically evaluate the therapeutic potential of semaglutide, a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist used for diabetes management, in OA and to elucidate its underlying molecular mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;&lt;strong&gt;Methods&lt;/strong&gt;&lt;/h3&gt;&lt;div&gt;We utilized a zebrafish cartilage injury repair model to screen and assess the impact of several hypoglycemic drugs on cartilage regeneration. OA was induced in C57BL/6 mice by destabilization of the medial meniscus (DMM) surgery. Using systemic &lt;em&gt;Glp-1r&lt;/em&gt; knockout mice, we systematically evaluated the effects of semaglutide on joint structure, function, and pain-related behaviors &lt;em&gt;in vivo&lt;/em&gt;. RNA sequencing was performed to explore the regulator effects of semaglutide on extracellular matrix metabolism, associated signaling pathways, and autophagy in IL-1β-stimulated primary mouse chondrocytes. To verify the functional loss, the GLP-1R antagonist Exendin (9-39) and the autophagy inhibitor Bafilomycin A1 were employed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;&lt;strong&gt;Results&lt;/strong&gt;&lt;/h3&gt;&lt;div&gt;Drug screening using a zebrafish cartilage injury model demonstrated that semaglutide exerted the most significant pro-regenerative effects, markedly promoting cartilage repair. In wild-type (WT) mice with DMM-induced OA, semaglutide treatment significantly improved gait abnormalities and mechanical hyperalgesia without significantly affecting body weight, and alleviated cartilage destruction, synovitis, and subchondral bone sclerosis associated with abnormal chondrocyte metabolism. However, GLP-1R inhibition or &lt;em&gt;Glp-1r&lt;/em&gt; knockout completely abolished the protective effects of semaglutide on chondrocyte metabolism and its therapeutic efficacy in OA. Moreover, &lt;em&gt;Glp-1r&lt;/em&gt; gene deficiency exacerbated cartilage degeneration and bone structural damage, indicating that GLP-1R signaling is indispensable for maintaining cartilage homeostasis. Mechanistically, semaglutide inhibited the AKT/mTOR pathway through GLP-1R activation, thereby reversing IL-1β- and DMM-induced autophagy suppression and restoring the balance of extracellular matrix metabolism in chondrocytes.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;&lt;strong&gt;Conclusion&lt;/strong&gt;&lt;/h3&gt;&lt;div&gt;Semaglutide exerts protective effects against OA by activating GLP-1R in chondrocytes, inhibiting the AKT/mTOR pathway, and enhancing chondrocyte autophagy. It alleviates abnormal cartilage metabolism in OA independently of body weight changes.&lt;/div&gt;&lt;div&gt;&lt;strong&gt;Translational potential of this study&lt;/strong&gt;: This study demonstrates, for the first time, that semaglutide exerts protective effects against OA independent of weight loss by directly activating chondrocyte GLP-1R, in","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101166"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13316188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone H3K18 lactylation: An exercise-induced epigenetic mechanism that inhibits osteoclast activity and protects against osteoporosis","authors":"Zhenru He,&nbsp;Yun Wu,&nbsp;Yuan You,&nbsp;Ting Li,&nbsp;Yilin Liao,&nbsp;Jingqiu Chen,&nbsp;Yuting Wang,&nbsp;Yue Sheng,&nbsp;Yaoyu Zhao,&nbsp;Wengwanyue Ye,&nbsp;Mengjie Yin,&nbsp;Peiqi Zhang,&nbsp;Ji Li,&nbsp;Huilin Tang,&nbsp;Jingyang Lou,&nbsp;Xiazhou Fu,&nbsp;Xiaohong Yang,&nbsp;Yaoting Ji","doi":"10.1016/j.jot.2026.101147","DOIUrl":"10.1016/j.jot.2026.101147","url":null,"abstract":"<div><h3>Objective</h3><div>Osteoclasts, through their excessive production, are the primary cause of postmenopausal osteoporosis. However, the influence of metabolism on osteoclastogenesis remains poorly understood. This study reveals that protein lactylation plays a critical role in osteoclast differentiation.</div></div><div><h3>Methods</h3><div>The ovariectomized (OVX) mouse model was used to investigate osteoporosis by examining glycolysis and lactate levels during osteoclast differentiation. Bone resorption was assessed through histomorphometric analysis. The effects of elevating lactate levels were tested both endogenously via exercise and exogenously through sodium lactate (NaLac) administration. Protein lactylation, focusing on histone modifications, was analyzed, and key osteoclastogenesis genes, including cathepsin K (<em>Ctsk</em>), matrix metalloproteinase 9 (<em>Mmp9</em>), and matrix metalloproteinase 12 (<em>Mmp12</em>), were quantified. The enzymes responsible for lactylation and delactylation were identified through cleavage under targets and tagmentation (CUT&amp;Tag) and RNA-Seq analyses.</div></div><div><h3>Results</h3><div>Our findings showed that glycolysis and lactate levels were reduced during osteoclast differentiation in the OVX model, despite increased bone resorption. Elevating lactate through exercise or sodium lactate supplementation increased protein lactylation and mitigated OVX-induced bone loss. Mechanistically, lactate enhanced histone H3 lysine-18 lactylation (H3K18la), which suppressed osteoclast differentiation by downregulating key osteoclastogenesis genes like <em>Ctsk, Mmp9</em>, and <em>Mmp12</em>. Alanyl-tRNA synthetase 1 (AARS1) was identified as the lactylation “writer” that mediates H3K18la, with sirtuin 6 (SIRT6) acting as an “eraser” in a regulatory circuit.</div></div><div><h3>Conclusions</h3><div>Lactate suppresses osteoclast differentiation and alleviates osteoporosis through histone H3K18 lactylation, which downregulates osteoclastogenic genes including <em>Ctsk, Mmp9</em>, and <em>Mmp12</em>. The dynamic regulation of H3K18la involves AARS1 as the lactylation “writer”and SIRT6 as an “eraser”.</div></div><div><h3>The translational potential of this article</h3><div>This study reveals an epigenetic mechanism by which lactate regulates osteoclast function and suggests that exercise-induced lactate elevation or lactate supplementation may represent a viable therapeutic strategy for postmenopausal osteoporosis.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101147"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13316643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}