Journal of Orthopaedic Translation最新文献

{"title":"Plasma-derived exosomes from obese knee osteoarthritis aggravate synovitis by promoting cellular senescence of synovial fibroblasts","authors":"Bin Zhang , Hailin Wang , Wanwan Qi , Song Li , Lun Tao , Xiuqin Peng , Yangli Xie , Liang Kuang , Peiyu Teng , Xiaoqi Zhang , Xiangdong Liu , Daibo Feng , Yunquan Gong , Wei Xiang , Tongyi Zhang , Bo Huang , Siru Zhou , Lin Chen , Yan Xiong , Zhenhong Ni","doi":"10.1016/j.jot.2025.11.007","DOIUrl":"10.1016/j.jot.2025.11.007","url":null,"abstract":"<div><h3>Objectives</h3><div>As the most important risk factor for knee osteoarthritis (OA), obesity is closely associated with the clinical symptoms of OA. This study aims to systematically analyze the exosomal RNAs signatures in the plasma of knee OA patients with different body mass index (BMI) and to investigate their pathological roles and potential mechanisms in synovitis.</div></div><div><h3>Methods</h3><div>The clinical information of 101 patients with knee OA was recorded and the correlation with BMI was analyzed. The plasma-derived exosomes were extracted from non-obese and obese patients with OA (EXOs<sup>Normal</sup> and EXOs<sup>Obese</sup>). The quantitative sequencing of exosomal RNAs in EXOs<sup>Normal</sup> and EXOs<sup>Obese</sup> was performed. Then, these plasma-derived exosomes were administered via intra-articular injection into C57BL/6 mice, and knee joint specimens were harvested for evaluation of synovitis and synovial fibroblast senescence. In another animal study, synovitis and synovial fibroblast senescence of destabilization of the medial meniscus surgery (DMM)-induced OA mice were assessed after intra-articular injection of plasma-derived exosomes extracted from diet-induced-obese and non-obese mice. Plasma-derived exosomes were used to treat H<sub>2</sub>O<sub>2</sub>-induced senescent fibroblasts and the cellular senescence signaling pathways were analyzed. Finally, we assessed the effect and mechanism of miR-192-5p on EXOs<sup>Obese</sup>-mediated cellular senescence.</div></div><div><h3>Results</h3><div>There was a positive relationship between BMI and WOMAC score, but a negative relationship between BMI and HSS score in knee OA patients. The RNAs sequencing identified 143 miRNAs (72 down-regulated and 71 up-regulated), 29 lncRNAs (15 up-regulated and 14 down-regulated), and 334 mRNAs (189 up-regulated and 145 down-regulated) that were significantly differentially expressed in plasma-derived exosomes between obese and non-obese OA patients. However, there were no differentially expressed circRNAs between two groups. Furthermore, KEGG and GO analysis of miRNAs showed that several cellular senescence-related pathways were significantly enriched in EXOs<sup>Obese</sup>. Intra-articular injection of EXOs<sup>Obese</sup> aggravated cellular senescence of synovial fibroblasts and synovitis in wild type mice. In the DMM-induced OA mice model, intra-articular injection of plasma-derived exosomes from obese mice aggravated synovial fibroblast senescence and synovitis. Additionally, EXOs<sup>Obese</sup> promoted cellular senescence of fibroblasts <em>in vitro</em>. We further found that the level of miR-192-5p in EXOs<sup>Obese</sup> was much higher compared to EXOs<sup>Normal</sup>. Mechanistically, miR-192-5p in EXOs<sup>Obese</sup> aggravated fibroblasts senescence through inhibition of autophagy by targeting ATG7.</div></div><div><h3>Conclusion</h3><div>Plasma EXOs<sup>Obese</sup> could exacerbate cellular senescence o","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101031"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of testosterone and alendronate coated membranes in osteoporotic fracture and defect model in rats and goats","authors":"Can Cui , Yik Lok Chung , Hei Yuet Wong , Pui Yan Wong , Chaoran Liu , Ning Zhang , Wing Hoi Cheung , Ronald Man Yeung Wong","doi":"10.1016/j.jot.2025.10.012","DOIUrl":"10.1016/j.jot.2025.10.012","url":null,"abstract":"<div><h3>Background</h3><div>Osteoporotic fractures present significant clinical challenges with associated risk of non-union. This study evaluates the efficacy of testosterone and alendronate-coated collagen membranes in accelerating osteoporotic fracture healing using rat and goat models.</div></div><div><h3>Methods</h3><div>Female Sprague–Dawley rats with ovariectomy-induced osteoporosis (n = 90) and ovariectomized Chinese mountain goats (n = 20) were assigned to treatment and control groups receiving either testosterone/alendronate-coated or control membranes at fracture or defect sites. Rats were euthanized at weeks 2, 4, and 8, and goats at days 30 and 60 post-operation. Assessments included radiographs, micro-CT, histology, immunohistochemistry, mechanical testing, and finite element analysis.</div></div><div><h3>Results</h3><div>In rats, the Ovariectomy (OVX)-Coated Membrane group exhibited significantly greater callus width at weeks 2, 4, and 8 compared to OVX-No Membrane (p < 0.01) and OVX-Control Membrane groups (p < 0.05). Callus area was 135 % larger at week 4 compared to control (p < 0.05). Micro-CT showed a 50 % increase in low-density bone volume (p < 0.05) and significant increases in high-density bone volume at week 8 (p < 0.01). Mechanical testing revealed a 20 % higher ultimate load (p < 0.05) and 35 % greater energy to failure (p < 0.001) in the treatment group. Immunohistochemistry demonstrated a 30 % increase in VEGF expression and a significant elevation in osteoblast numbers at early time points (p < 0.05). Serum testosterone levels were significantly elevated in treated rats at week 2 (p < 0.05) (Fig.5A). In goats, no significant differences in callus parameters were observed at day 30. However, by day 60, the OVX-Coated group showed a 24 % greater callus width (p < 0.05), 135 % larger callus area , and 19 % higher callus index. Micro-CT analysis revealed a significant increase in high-density bone volume (p < 0.01), BV/TV (p < 0.01), and trabecular number (p < 0.05).Mechanical testing indicated a trend toward higher ultimate load. Finite element analysis showed a 28 % more uniform stress distribution and significantly lower deformation under 800 N load, suggesting enhanced biomechanical stability. Histology confirmed increased trabecular bone formation, collagen fiber proliferation, and osteoclast activity at day 60 (Fig.5B).</div></div><div><h3>Conclusion</h3><div>These findings suggest that testosterone and alendronate-coated collagen membranes significantly accelerate osteoporotic fracture healing by promoting angiogenesis, osteoblast activity, and balanced bone remodeling. Early effects are evident in rodents, with later but robust healing in large animal models.</div></div><div><h3>The translational potential of this article</h3><div>The dual anabolic and antiresorptive strategy enhances bone quality and mechanical strength, supporting its potential clinical translation for im","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101020"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of α2-adrenergic receptors as a therapeutic strategy for immune rejection in post-surgery osteosarcoma recurrence treatment","authors":"Yan-Hong Pei , Zhen Wang , Yu-Shu Zheng , Zi-Ying Wang , Cheng-Wei Cao , Hai-Jie Liang , Bo-Yang Wang , Zhi-Jian Jin , Shan-Yi Lin , Lin-Xi Chen , Wei Guo , Meng Xu","doi":"10.1016/j.jot.2025.10.001","DOIUrl":"10.1016/j.jot.2025.10.001","url":null,"abstract":"<div><h3>Background</h3><div>The clinical treatment of Osteosarcoma (OS) faces major barriers due to the risk of tumor recurrence. Immunotherapy utilizing immune checkpoint blockade (ICB) antibodies has exhibited promise in inducing tumor rejection and providing clinical benefits for patients among various tumor types. However, tumors often develop resistance to immune rejection. Given the limitations of current therapies, there is an urgent need to explore novel therapeutic strategies to enhance anti-tumor immunity and prevent recurrence. This study aims to investigate the potential of α2-adrenergic receptor (α2-AR) agonists, delivered via a thermo-sensitive hydrogel (PLGA-PEG-PLGA), as a therapeutic strategy to combat immune rejection and tumor recurrence in osteosarcoma.</div></div><div><h3>Methods</h3><div>In this study, we investigated the anti-tumor effects of α2-AR agonists using a thermo-sensitive PLGA-PEG-PLGA hydrogel as a drug delivery system. The hydrogel was loaded with the α2-AR agonist UK14,304 and evaluated for its efficacy and biosafety <em>in vitro</em> and <em>in vivo</em>. <em>In vitro</em> experiments included cell viability assays (CCK-8), scratch wound healing assays, and Transwell assays to assess the impact of UK14,304 on OS cell lines. For <em>in vivo</em> studies, a subcutaneous OS xenograft mouse model was established using BALB/c nude and immunocompetent BALB/c mice. Tumor recurrence and growth were monitored after surgical resection and treatment with the hydrogel-agonist formulation. Proteomic analysis of tumor immune microenvironment (TME), Metascape, STRING, Cytoscape, TCGA and GTEx databases were performed to elucidate the underlying mechanisms of the anti-tumor effects.</div></div><div><h3>Results</h3><div>We evaluated the anti-tumor effects of α2-AR agonists (specifically UK14,304) loaded into a thermo-sensitive PLGA-PEG-PLGA hydrogel both <em>in vitro</em> and <em>in vivo</em>. <em>In vitro</em> experiments using OS cell lines (K7M2, 143b, and Khos) showed that UK14,304 did not significantly affect cell viability, migration, or invasion, indicating minimal direct cytotoxicity. <em>In vivo</em> studies using immunocompetent BALB/c mice demonstrated a significant reduction in tumor recurrence and growth when treated with UK14,304-loaded hydrogels compared to controls, highlighting an immune-mediated anti-tumor effect. Proteomic analysis of TME revealed that the anti-tumor mechanism involves the activation of CD8<sup>+</sup> T cells and TCR signaling pathways, with ITGAL identified as a central regulatory factor. Additionally, bioinformatics analysis suggested the involvement of LLPS in enhancing TCR signaling. Correlation analysis with TCGA and GTEx databases further indicated that the identified proteins (e.g., MSN, TOLLIP, ITGAL) are associated with improved clinical outcomes.</div></div><div><h3>Conclusion</h3><div>Overall, our results demonstrate that α2-AR agonists may serve as a potential drug for a prospe","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101009"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting synovial inflammation in knee osteoarthritis: translational insights for diagnosis and therapy","authors":"Ali Mobasheri ,&nbsp;Francisco Castro-Domínguez ,&nbsp;Oreste Gualillo ,&nbsp;Stefan Kluzek ,&nbsp;Silvia Paz Ruiz ,&nbsp;Raquel Largo","doi":"10.1016/j.jot.2025.10.004","DOIUrl":"10.1016/j.jot.2025.10.004","url":null,"abstract":"<div><div>Synovial inflammation is a central feature of knee osteoarthritis (OA), linking systemic and local pathogenic pathways with clinical outcomes. This review synthesises current knowledge on synovial structure and function, and the molecular mechanisms that drive synovitis, including metaflammation, mechanoflammation, mechanotransduction, and immune cell polarisation. It further explores how these processes contribute to structural degeneration, pain, and disease progression. Diagnostic approaches are discussed, with emphasis on biochemical biomarkers, imaging modalities, and the limited reliability of pain alone as a disease marker. By integrating clinical phenotypes with molecular endotypes, the review features how precision medicine can reshape OA care. Therapeutic strategies are presented across the translational spectrum, from oral and intra-articular drugs in clinical use to emerging investigational therapies, multitargeting approaches, and novel gene therapies. This review advocates for phenotype- and endotype-informed interventions as a pathway to more effective and personalised management of synovitis-driven knee OA. The translational value of this work lies in integrating molecular mechanisms with clinical strategies to guide early diagnosis, refine therapeutic targeting, and inform the design of future trials.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101012"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global to local burdens, inequalities, and achievable frontiers of child and adolescent malignant neoplasm of bone and articular cartilage across 953 countries and sublocations, 1980–2040, with deep learning-based forecasts","authors":"Wenxiang Cai ,&nbsp;Yaling Wu ,&nbsp;Mingyang Xue ,&nbsp;Yihang Chu ,&nbsp;GBD 2021 Global to Local Child and Adolescent MNBAC Collaborators,&nbsp;Salman Rawaf ,&nbsp;Marilyn M. Bui ,&nbsp;Javier Martín Broto ,&nbsp;Heping Zhang ,&nbsp;Lukasz Szarpak ,&nbsp;Liming Pan ,&nbsp;Baozhen Huang ,&nbsp;Yiming Xiong ,&nbsp;Fei Li ,&nbsp;You Zeng ,&nbsp;Kai Chen ,&nbsp;Claire Chenwen Zhong ,&nbsp;Hao Peng ,&nbsp;Pengpeng Ye ,&nbsp;João Conde ,&nbsp;Wenyi Jin","doi":"10.1016/j.jot.2025.101042","DOIUrl":"10.1016/j.jot.2025.101042","url":null,"abstract":"<div><h3>Background</h3><div>Malignant neoplasm of bone and articular cartilage (MNBAC), a major cause of cancer-related mortality, disproportionately impacts children and adolescents. However, comprehensive and future-oriented studies are still lacking.</div></div><div><h3>Methods</h3><div>We systematically analyzed global-to-subnational MNBAC burdens, inequalities, and ideal achievable frontiers among those under 20 years old across 953 locations from 1980 to 2021. An advanced attention-based deep-learning pipeline was created for precise forecasting.</div></div><div><h3>Results</h3><div>From 1990 to 2021, the global prevalence and incidence rate of MNBAC among those aged &lt;20 years increased by 14.7 % and 14.3 %, respectively, leading to 139,154 prevalent cases by 2021. This disproportionately affected males and increased progressively with age, peaking in adolescents aged 15–19 years. Despite a slight global decline in MNBAC mortality, notable increases were observed in low-middle SDI region. 87.3 % of countries and 93.8 % of subnational locations experiencing increased mortality were situated in low to middle SDI regions, exemplified by Tokelau (377.8 %) and Indonesia's West Papua (148.6 %). Concurrently, the global YLD/YLL ratio for those &lt;20 years increased, reflecting the ongoing transition from fatal to non-fatal burdens. This shift mainly impacted socio-economically advantaged settings, as 61 % of the top 100 countries were categorized as high and high-middle SDI. However, substantial gaps remain globally, with at least 94.1 % of countries and 81.4 % of subnational locations failing to meet achievable frontiers by 2021. Forecasts to 2040 anticipate further increases in incidence and stagnation in mortality, alongside widening disparities. Approximately 60.0 % of 672 subnational locations are forecasted to exhibit rising prevalence, with 41.2 % in the UK. By 2040, 30.0 % of the top 100 high-prevalence subnational locations will likely be in Sub-Saharan Africa, including 56 % in the UK. Mortality rates are forecasted to remain highest in low SDI region, especially in Eastern Sub-Saharan Africa, accounting for 47.7 % in Kenya alone.</div></div><div><h3>Conclusion</h3><div>The MNBAC burden remains high, especially among adolescents, with anticipated increases in lower-income areas, necessitating targeted healthcare policies and increased investment.</div></div><div><h3>The Translational Potential of this Article</h3><div>This study highlights the growing global burden of MNBAC and the urgent need for age-specific prevention, early detection, and equitable access to healthcare. Enhancing cancer registries, expanding financial protection, and integrating MNBAC management into national cancer control strategies could help reduce disparities and improve outcomes for affected children and adolescents.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101042"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in organoids and organs-on-chips for accelerating orthopaedic innovation and translation","authors":"Zhong Alan Li ,&nbsp;Yiting Lei ,&nbsp;Long Bai ,&nbsp;Jiacan Su ,&nbsp;Rocky S. Tuan","doi":"10.1016/j.jot.2025.101043","DOIUrl":"10.1016/j.jot.2025.101043","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101043"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causal neurodevelopmental origins of scoliosis: Multi-omics Mendelian randomization reveals brain–region–specific pathways and protein mediators","authors":"Shuhao Zhang ,&nbsp;Sisi Lu ,&nbsp;Shiyu Chen ,&nbsp;Xiangxiang Pan ,&nbsp;Dongdong Xia ,&nbsp;Lue Liu ,&nbsp;Chenglong Xie ,&nbsp;Majid Nisar ,&nbsp;Aimin Wu ,&nbsp;Xiaolei Zhang ,&nbsp;Xiangyang Wang ,&nbsp;Chongan Huang","doi":"10.1016/j.jot.2025.09.010","DOIUrl":"10.1016/j.jot.2025.09.010","url":null,"abstract":"<div><h3>Background</h3><div>The causal relationship between early-life central nervous system (CNS) infections and adolescent idiopathic scoliosis (AIS) remains unresolved, with limited evidence on mediating mechanisms linking neuroanatomical changes to spinal deformity.</div></div><div><h3>Method</h3><div>Through three longitudinal cohorts (n = 57875) and two-step Mendelian randomization (MR) integrating neuroimaging genomics (UK Biobank) and proteomics, we dissected causal pathways from childhood viral encephalitis (VE) to scoliosis. We employed inverse-variance weighted (IVW), MR-Egger regression, and sensitivity analyses (MR-PRESSO) to control for pleiotropy and reverse causation.</div></div><div><h3>Results</h3><div>Childhood VE was associated with a 3.6-fold increased risk of scoliosis (HR = 3.604, 95 % CI: 3.121–4.163, P = 0.001), with lesions in the corpus callosum and cerebellum showing the strongest effects. MR analysis identified seven imaging-derived phenotypes (IDPs) causally linked to scoliosis, including grey matter volume in the left thalamus (OR = 1.451) and isotropic free water fraction in the cerebellar peduncle (OR = 2.408). Mediation MR revealed that brain protein ERBB4 and cerebrospinal fluid protein LBP mediated 34.9 % of the total effect (β = −0.181), highlighting their role in bridging neuroinflammation to spinal deformity.</div></div><div><h3>Conclusion</h3><div>This study offers suggestive evidence for a causal pathway from childhood CNS infections to scoliosis, mediated by specific brain-region damage and protein biomarkers.</div></div><div><h3>The translational potential of this article</h3><div>Clinically, the results support the implementation of scoliosis screening programs in children recovering from CNS infections.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101006"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial DNA released from pyroptotic synovial macrophages via DDIT3-mediated mitophagy aggravates osteoarthritis progression","authors":"Chang Yang ,&nbsp;Jin Ke ,&nbsp;Qiongdong Xu ,&nbsp;Wei Dong ,&nbsp;Wenqian Yu ,&nbsp;Yan Wang ,&nbsp;Jiawei Wang","doi":"10.1016/j.jot.2025.101036","DOIUrl":"10.1016/j.jot.2025.101036","url":null,"abstract":"<div><h3>Objective</h3><div>Emerging evidence has shown that inflammatory synovial macrophage and anabolism-impaired chondrocytes play essential roles in osteoarthritis (OA). The present work aims at uncovering the pathogenic mechanism of how the damage-associated molecular patterns (DAMPs) released from inflammatory synovial macrophage promote extracellular matrix (ECM) degradation of chondrocytes and developing feasible strategies to counter its detrimental effects.</div></div><div><h3>Methods</h3><div>We identified pyroptosis of synovial macrophages in the synovium of OA human and mouse. The effect and mechanism of mitochondrial DNA (mtDNA) released from pyroptotic synovial macrophage in ECM degradation of chondrocytes and cartilage degeneration was further explored in cellular and animal models. Finally, the ameliorative effect of folic acid-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles in OA was elucidated by <em>in vivo</em> experiments.</div></div><div><h3>Results</h3><div>Mitochondrial dysfunction in synovial macrophages leads to the release of mtDNA into the cytoplasm, which promotes macrophage pyroptosis, thereby facilitating extracellular release of mtDNA and creating an inflammatory microenvironment unfavorable to cartilage in OA. DDIT3 deficiency inhibits mtROS production by enhancing PINK1/Parkin-dependent mitophagy, which constraining the mtDNA release into the cytoplasm. The decreased cytosolic mtDNA, in turn, dampens macrophage pyroptosis. <em>In vivo</em>, DDIT3 deficiency significantly alleviates synovial inflammation and cartilage degeneration in OA progression, and targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles mimics the protective effects of DDIT3 deficiency against OA progression.</div></div><div><h3>Conclusions</h3><div>Our findings identified the pathological role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA, and demonstrated the efficacy of using folic acid-modified PLGA nanoparticles as a delivery for OA treatment.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the pivotal role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA. Targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles might serve as a potential therapeutic target for alleviating cartilage degeneration in OA.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101036"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteoarthritis pathogenesis Unveiled: DMT1 drives autophagy-dependent ferroptosis through a mir-17-5p/NEDD4 regulatory axis","authors":"Guanglei Zhao ,&nbsp;Yue Shen ,&nbsp;Jingchun Ma ,&nbsp;Xin Huang ,&nbsp;Jie Chen ,&nbsp;Jingsheng Shi ,&nbsp;Jun xia ,&nbsp;Siqun Wang ,&nbsp;Gangyong Huang ,&nbsp;Weigang Wu","doi":"10.1016/j.jot.2025.11.002","DOIUrl":"10.1016/j.jot.2025.11.002","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA), a debilitating joint disorder lacking disease-modifying therapies, involves ferroptosis-an iron-dependent cell death. While ferroptosis contributes to OA progression, its autophagy-dependent mechanisms remain undefined. This study reveals DMT1 (divalent metal transporter 1) as a central regulator of autophagic ferroptosis in OA pathogenesis.</div></div><div><h3>Methods</h3><div>OA-related ferroptosis genes were screened by LASSO regression and random forest models. IL-1β/Erastin-stimulated chondrocytes and DMM-induced OA mice were used to investigate DMT1 function. Ferroptosis and autophagy were assessed by lipid peroxidation, autophagic flux, Western blot, and modulators. Micro-CT, OARSI scoring and behavioral tests evaluated joint damage. Regulatory mechanisms were examined by miR-17-5p mimic, luciferase assays and NEDD4-mediated ubiquitination.</div></div><div><h3>Results</h3><div>DMT1 was upregulated in OA cartilage and IL-1β-stimulated chondrocytes, correlating with ferroptosis activation. Genetic DMT1 suppression attenuated ferroptosis <em>in vitro</em> and <em>in vivo</em>, whereas overexpression exacerbated lipid peroxidation and impaired cartilage repair post-DMM surgery in mice. Mechanistically, DMT1 overexpression activated autophagy, linking it to ferroptosis execution – pharmacological autophagy inhibition reduced DMT1-driven ferroptosis, while autophagy inducers amplified its effects.</div></div><div><h3>Conclusions</h3><div>We identified a DMT1–autophagy–ferroptosis axis as a critical OA mechanism. Ferroptosis inhibitors and upstream regulators (miR-17-5p, NEDD4) show promise as disease-modifying strategies for OA.</div></div><div><h3>The translational potential of this article</h3><div>This study not only elucidates a novel DMT1-autophagy-ferroptosis axis but also identifies NEDD4 as upstream therapeutic targets. The demonstration that Lip-1 treatment alleviates DMT1-driven OA exacerbation <em>in vivo</em> highlights translational potential of ferroptosis inhibition as a disease-modifying strategy for OA. Moreover, NEDD4 overexpression represents promising gene-based interventions with potential for precision therapy in OA.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101026"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanotransduction-driven macrophage polarization via Integrin-SRC-STAT6 pathway in distraction osteogenesis","authors":"Xu Yan ,&nbsp;Haixing Wang ,&nbsp;Xuan Lu ,&nbsp;Linlong Li ,&nbsp;Shanshan Bai ,&nbsp;Zitong Li ,&nbsp;Han Su ,&nbsp;Rongjie Wu ,&nbsp;Hui Chen ,&nbsp;Yinuo Fan ,&nbsp;Jiting Liu ,&nbsp;Xinkun Zhang ,&nbsp;Lichun Xie ,&nbsp;Ling Qin ,&nbsp;Gang Li ,&nbsp;Sien Lin","doi":"10.1016/j.jot.2025.10.016","DOIUrl":"10.1016/j.jot.2025.10.016","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Mechanical stimuli are indispensable for bone regeneration. Distraction osteogenesis (DO) is a widely used clinical technique for limb lengthening and bone defect repair; however, its specific mechanobiological mechanisms remain unclear. Macrophages play crucial regulatory roles throughout bone fracture healing. Recent studies indicate that macrophages are mechanosensitive and can modulate the local immune microenvironment in response to mechanical cues. This study aims to investigate how macrophages respond to mechanical stimulation and regulate bone regeneration during DO.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Animal models of DO (with external fixation) and fracture healing (with internal fixation) were established to compare bone regeneration under different mechanical conditions. Immunohistochemistry (IHC) was used to quantify M1 and M2 macrophage infiltration. An &lt;em&gt;in vitro&lt;/em&gt; model of cyclic mechanical stretch (10 %, 0.5 Hz, 12 h) was applied to RAW264.7 cells to study macrophage polarization. Flow cytometry, PCR, and western blot were used to assess macrophage phenotypes. An indirect co-culture system was employed to evaluate the effect of mechanically stimulated M2 macrophages on osteogenic differentiation. Single-cell RNA sequencing analysis of public data was performed to identify key biological processes in macrophage subpopulations during DO. Western blot and immunofluorescence were used to measure expression and phosphorylation levels of SRC and STAT-6. Pathway inhibitors were applied to elucidate regulatory mechanisms. &lt;em&gt;In vivo&lt;/em&gt;, Saracatinib and TGF-β were administered locally in DO models. Bone regeneration was evaluated using micro-CT, mechanical testing, and histology.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;DO significantly enhanced M2 macrophage polarization at 1st, 2nd, and 4th week post-surgery compared to controls. Cyclic stretch promoted M2 polarization &lt;em&gt;in vitro&lt;/em&gt; and increased secretion of TGF-β and IL-10. Mechanically induced macrophages enhanced osteoblast differentiation in co-culture. Mechanical activation of the Integrin-SRC-STAT6 pathway drove M2 polarization. Local SRC inhibition suppressed M2 polarization and impaired bone regeneration in DO, which was partially rescued by TGF-β supplementation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Mechanical stimulation during DO promotes M2 macrophage polarization via the Integrin-SRC-STAT6 pathway. TGF-β appears to be a key cytokine secreted by mechanically induced M2 macrophages that facilitates osteogenesis. These findings reveal a novel mechano-immune regulatory axis that supports bone regeneration in DO.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;This research confirms the core concept of \"mechano-immunoregulation\" and identifies actionable therapeutic targets, enabling the development of targeted therapies for refractory bone defects by modulating the integrin-β1/SRC/STAT6 pathway and TGF-β1 to enh","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101024"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}