Journal of Orthopaedic Translation最新文献

{"title":"Acetyl-CoA synthase 1 mediates metabolic reprogramming to promote proliferation and metastasis of osteosarcoma","authors":"Xiuming He ,&nbsp;Mengliang Luo ,&nbsp;Chenyang Wang ,&nbsp;Lingkai Kong ,&nbsp;Jianglong Li ,&nbsp;Jianye Tan ,&nbsp;Junhao Chen ,&nbsp;Yi Nie ,&nbsp;Hantao Chen ,&nbsp;Zhipeng Zou ,&nbsp;Zexin Su ,&nbsp;Lijun Lin","doi":"10.1016/j.jot.2026.101052","DOIUrl":"10.1016/j.jot.2026.101052","url":null,"abstract":"<div><h3>Background</h3><div>Although the combination of surgery and chemotherapy has dramatically improved the prognosis of patients with osteosarcoma (OS), the prognosis of OS patients with metastatic or recurrent tumors remains poor. Here, we found significant upregulation of the acetyl-CoA synthesis-related pathway in OS patients with metastases.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis identified ACSS1 as a key metastasis-related gene in OS, with clinical OS specimens validating its association with poor prognosis. In vitro, ACSS1 knockdown in 143B and SJSA1 cells was used to assess proliferation (EdU, colony formation), migration/invasion (Transwell, 3D spheroids), and mitochondrial function (Seahorse, TEM). Untargeted metabolomics and transcriptomics characterized ACSS1-regulated lipid pathways, while <em>in vivo</em> validation employed nude mouse models of orthotopic xenograft and tail vein metastasis.</div></div><div><h3>Results</h3><div>Notably, the expression of Acetyl-coenzyme A synthetase 1 (ACSS1), an enzyme critical for acetyl-CoA synthesis, was negatively correlated with pulmonary metastasis-free and overall survival in OS patients. ACSS1 depletion decreases the metastatic ability and energy metabolism of OS cells, resulting in reactive oxygen species (ROS) accumulation. Mechanistically, ACSS1 exerts acetyl-CoA synthetase activity and maintains dynamic homeostasis of acetyl-CoA metabolism in the mitochondria. It promotes lipid synthesis and regulates metabolic homeostasis by inducing stearoyl coenzyme A desaturase (SCD) expression, which can fuel the metastasis of OS cells and promotes their survival.</div></div><div><h3>Conclusion</h3><div>ACSS1 drives OS metastasis by maintaining mitochondrial acetyl-CoA homeostasis and activating SCD-dependent lipid synthesis. Targeting the ACSS1/SCD axis offers a promising strategy for metastatic OS.</div></div><div><h3>The translational potential of this article</h3><div>This study reveals the therapeutic potential of targeting ACSS1/SCD axis, for example, by specific small-molecule inhibitors in treating osteosarcoma metastasis, in addition to conventional chemotherapies.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101052"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147600341","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":"HIF1A transcriptionally activates CDKN1A to drive ferroptosis in skeletal muscle ischaemia-reperfusion injury","authors":"Ming Zhou ,&nbsp;Kai Wang ,&nbsp;Yesheng Jin ,&nbsp;Jinquan Liu ,&nbsp;Yuan Xue ,&nbsp;Yapeng Wang ,&nbsp;Xueyuan Jia ,&nbsp;Hao Liu ,&nbsp;Peng Wang ,&nbsp;Zeqing Li ,&nbsp;Xiaoyun Pan ,&nbsp;Yunhong Ma ,&nbsp;Yongjun Rui","doi":"10.1016/j.jot.2026.101055","DOIUrl":"10.1016/j.jot.2026.101055","url":null,"abstract":"<div><h3>Background</h3><div>Skeletal muscle ischaemia-reperfusion (I/R) injury involves complex redox dysregulation with limited treatments. Although ferroptosis contributes to other organ I/R injuries, its role and regulation in skeletal muscle remain unclear. This study aimed to investigate the role and regulatory mechanism of ferroptosis in skeletal muscle I/R injury, specifically focusing on whether hypoxia-inducible factor 1 alpha (HIF1A) transcriptionally activates cyclin-dependent kinase inhibitor 1a (CDKN1A/p21) to drive this process.</div></div><div><h3>Methods</h3><div>We employed integrative transcriptomics and Cleavage Under Targets and Tagmentation (CUT&amp;Tag, a chromatin mapping technique) sequencing in murine I/R models. Genetic inhibition (<em>Hif1a</em> siRNA) and pharmacological inhibition (LW6) were utilized <em>in vitro</em> and <em>in vivo</em>. <em>Cdkn1a</em> overexpression was performed for rescue experiments. Ferroptosis was assessed by examining mitochondrial ultrastructure, quantifying lipid peroxidation, and evaluating the expression of key proteins: glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and prostaglandin-endoperoxide synthase 2 (PTGS2). Clinical relevance was evaluated by co-expression analysis of HIF1A and CDKN1A in human I/R-affected muscle biopsies.</div></div><div><h3>Results</h3><div>HIF1A directly bound to the <em>Cdkn1a</em> promoter during nuclear translocation, upregulating its expression. Both HIF1A inhibition (genetic or pharmacological) significantly attenuated ferroptosis, evidenced by preserved mitochondria, reduced lipid peroxidation, and normalized ferroptosis-related protein levels. Crucially, <em>Cdkn1a</em> overexpression reversed the anti-ferroptotic effects of <em>Hif1a</em> knockdown, confirming CDKN1A as a key downstream effector. Strong positive co-expression of HIF1A and CDKN1A was observed in human I/R biopsies (Spearman's r = 0.543, p = 0.006). Mechanistically, the HIF1A-CDKN1A axis exacerbated redox stress via glutathione depletion and intracellular free iron accumulation.</div></div><div><h3>Conclusion</h3><div>Our findings establish HIF1A as a context-dependent ferroptosis amplifier in skeletal muscle I/R injury, acting through direct transcriptional activation of <em>Cdkn1a</em>. This HIF1A-CDKN1A axis drives ferroptosis by disrupting redox homeostasis. Targeting HIF1A and CDKN1A within this pathway provides two complementary molecular entry points for mitigating skeletal muscle I/R injury.</div></div><div><h3>The Translational Potential of this Article</h3><div>Targeting the HIF1A-CDKN1A axis offers a promising therapeutic approach to reduce skeletal muscle damage and improve clinical outcomes after ischaemia-reperfusion injury.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101055"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147306954","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":"Vitamin D deficiency and disease conditions relevant to: Orthopaedic translation","authors":"Dinayinie Ekanayake Mudiyanselage ,&nbsp;Charles Edward Ouyang ,&nbsp;Rebekah Ding Jin ,&nbsp;SriHarshidha Velmurugan ,&nbsp;Yunze Jiang ,&nbsp;Jiashi Sun ,&nbsp;Daqing Ma","doi":"10.1016/j.jot.2026.101061","DOIUrl":"10.1016/j.jot.2026.101061","url":null,"abstract":"<div><div>Vitamin D, traditionally known for its role in calcium-phosphate homeostasis and bone health, is now recognised as a pleiotropic hormone with critical effects on multiple physiological processes. It exists primarily as ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃), which are biologically inactive until undergoing a sequential hydroxylation in the liver to form 25-hydroxyvitamin D (calcidiol), and subsequently in kidney to form the active metabolite 1,25-dihydroxyvitamin D (calcitriol). By engaging the vitamin D receptor, it exerts immunomodulatory, neuroprotective, and anti-frailty functions. Deficiency in vitamin D has been implicated in a wide range of disorders, including musculoskeletal weakness, frailty, cognitive decline, autoimmune diseases, and respiratory infections. Vitamin D deficiency affects nearly half of the global population and remains a widespread public health challenge, and effective interventions such as food fortification and targeted supplementation should be prioritized in future strategies.</div></div><div><h3>The translational potential of this article</h3><div>Vitamin D deficiency represents a modifiable risk factor with implicated effects across systemic, neurocognitive and musculoskeletal systems. Epidemiological evidence links deficiency to increased risk of infection, cognitive decline, frailty and orthopaedic morbidity. In orthopaedic and geriatric populations, maintaining sufficient vitamin D supplementation may reduce fracture and fall risk as well as postoperative complications and infections. These factors are also influenced by vitamin D deficiency-related effects on neurocognition. Vitamin D status may also be relevant in the management of infectious diseases, including respiratory illnesses and COVID-19. This review also discusses mechanistic and practical rationales for clinical translation. Potential interventions include vitamin D co-supplementation, dietary fortification and optimised sun exposure. However, limitations in existing randomised trials underscore the need for consistency in dosing, appropriate formulation, targeted population, as well as baseline deficiency progression status. These insights can guide clinicians, public health policy makers and researchers in developing evidence-based protocols and interventions to reduce vitamin D deficiency-related morbidity.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101061"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147348504","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":"Macrophage iron overload promotes osteoporosis via Cxcl3- and Cxcl7-mediated paracrine signaling in ovariectomized mice","authors":"Pin Gong ,&nbsp;Yuan Ma ,&nbsp;Xiaohu Wu ,&nbsp;Naiqian Cui ,&nbsp;Xin Guan ,&nbsp;Xianrong Zhang ,&nbsp;Bin Yu","doi":"10.1016/j.jot.2025.09.012","DOIUrl":"10.1016/j.jot.2025.09.012","url":null,"abstract":"<div><h3>Background</h3><div>Iron is an essential element for fundamental biological processes, but excess iron contributes to toxicity and is associated with osteoporosis in iron-overload disorders. Although iron chelators are routinely used to treat hematologic iron-overload conditions, emerging evidence suggests their potential applicability in osteoporosis treatment.</div></div><div><h3>Method</h3><div>Iron chelators were administered to ovariectomized (OVX) mice to investigate the relationship between iron overload and osteoporosis. Iron accumulation in macrophages was demonstrated through iron and F4/80 co-staining. We analyzed single-cell RNA sequencing data and utilized a Cxcr2 inhibitor to identify the pro-adipogenic factor. A single-gene knockdown approach was employed to confirm that the Cxcl3/Cxcl7-Cxcr2 paracrine signaling pathway promotes adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Finally, the effect of Cxcr2 blockade was verified in OVX mice.</div></div><div><h3>Result</h3><div>We identified iron accumulation in bone marrow-derived macrophages (BMDMs) of ovariectomized (OVX) mice, which drives BMSCs differentiation toward adipocytogenesis through Cxcl3- and Cxcl7-mediated paracrine activation of Cxcr2 on BMSCs, thereby promoting osteoporosis progression. Iron chelators reversed iron overload in BMDMs, alleviating bone marrow adiposity and bone loss.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that iron overload in BMDMs acts as the novel pathogenic driver in OVX-induced bone loss, wherein the Cxcl3/Cxcl7-Cxcr2 axis serves as the critical signaling nexus between iron-laden BMDMs and adipogenic differentiation of BMSCs. Iron chelation or Cxcr2 blockade therapy may represent a potential treatment for estrogen-deficiency osteoporosis.</div></div><div><h3>The translational potential of this article</h3><div>Our research elucidates the mechanisms by which iron chelators and Cxcr2 inhibitors may prevent or treat estrogen-deficiency osteoporosis. Future translational research about iron chelators or Cxcr2 blockade may provide new strategies for the prevention and treatment of postmenopausal osteoporosis.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101008"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419517","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":"The PTBP1-EZH2-DOCK2 axis promotes M1 microglial polarization and exacerbates neuronal apoptosis following spinal cord injury","authors":"Chunhe Sha,&nbsp;Feng Pan,&nbsp;Xiaodong Liu,&nbsp;Zhiqing Wang,&nbsp;Hongbin Dai,&nbsp;Kai Huang","doi":"10.1016/j.jot.2025.10.008","DOIUrl":"10.1016/j.jot.2025.10.008","url":null,"abstract":"<div><h3>Objective</h3><div>Microglial M1 polarization plays a critical role in secondary injury following spinal cord injury (SCI) by promoting the release of inflammatory factors and inducing neuronal apoptosis. This study aims to investigate the regulatory mechanism of the polypyrimidine tract-binding protein 1 (PTBP1)-enhancer of zeste homolog 2 (EZH2)-dedicator of cytokinesis 2 (DOCK2) axis in microglial polarization and to analyze its impact on neuronal apoptosis, thereby uncovering potential mechanisms underlying SCI pathophysiology.</div></div><div><h3>Methods</h3><div>A SCI rat model was established, with expression regulated via lentiviral infection. Motor function was evaluated using behavioral assessments, while hematoxylin and eosin (HE) staining, immunofluorescence (IF), co-staining of TUNEL/NeuN, Nissl staining, and Western blotting (WB) were performed to evaluate spinal cord pathology, microglial polarization, inflammation, and neuronal apoptosis, respectively. In HMC3 cells, flow cytometry, IF, WB, actinomycin D treatment, RIP-qPCR, ChIP-qPCR, and dual-luciferase reporter assays were utilized to investigate the regulatory interactions among PTBP1, EZH2, and DOCK2 and their impacts on microglial polarization. Co-culture of HMC3 with SH-SY5Y cells were conducted to evaluate the effect of microglial polarization on neuronal apoptosis.</div></div><div><h3>Results</h3><div>In both SCI rats and lipopolysaccharide (LPS)-treated HMC3 cells, expression of PTBP1, EZH2, and DOCK2 was significantly upregulated. Mechanistic analysis revealed that PTBP1 enhanced EZH2 mRNA stability, increasing EZH2 expression. Moreover, EZH2 promoted DOCK2 transcription in manner independent of the polycomb repressive complex 2 (PRC2), histone methylation, and DNA methylation. Inhibition of the PTBP1-EZH2-DOCK2 axis promoted the shift of HMC3 cells toward M2 polarization. Restoration of the M1/M2 microglial balance attenuated neuronal apoptosis and inflammatory responses. <em>In vivo</em> studies further confirmed that inhibiting this pathway ameliorated motor function and facilitated SCI recovery.</div></div><div><h3>Conclusion</h3><div>PTBP1 enhances EZH2 mRNA stability to upregulate DOCK2 transcription, driving microglial polarization toward the M1 phenotype. This mechanism aggravates neuronal apoptosis and inflammation, ultimately contributing to the progression of SCI pathology.</div></div><div><h3>The Translational Potential of this Article</h3><div>This study reveals the PTBP1-EZH2-DOCK2 axis as a potential molecular basis for intervening in aberrant microglial polarization and developing novel therapeutic targets for SCI. This research possesses significant potential for clinical translation.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101016"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420094","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":"A beneficial effect of a novel DKK1 monoclonal antibody and its sequential alendronate on bone and muscle properties of orchiectomized mice","authors":"Yanye Wang ,&nbsp;Lei Sun ,&nbsp;Lingyang Meng ,&nbsp;Bingna Zhou ,&nbsp;Dapeng Zhang ,&nbsp;Weizhu Qian ,&nbsp;Lijia Cui ,&nbsp;Qian Zhang ,&nbsp;Ou Wang ,&nbsp;Yan Jiang ,&nbsp;Weibo Xia ,&nbsp;Xiaoping Xing ,&nbsp;Mei Li","doi":"10.1016/j.jot.2025.10.014","DOIUrl":"10.1016/j.jot.2025.10.014","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Insights into basic bone biology and genetic disorders have led to advances in the treatment of osteoporosis. However, new drugs for the treatment of osteoporosis in men remain insufficient. We investigated the efficacy of a novel anti-Dkk1 monoclonal antibody (Dkk1-mAb) and its sequential alendronate treatment in a mouse model of osteoporosis induced by orchiectomy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A specific Dkk1-mAb was generated using the hybridoma technology. A total of 40 male C57BL/6 mice aged 12 weeks underwent orchidectomy or sham surgery. At 8 weeks postoperatively, the orchiectomized mice were randomly divided into 4 groups (8 in each group) to receive treatment of Dkk1-mAb, alendronate, Dkk1-mAb followed by alendronate, or placebo. After 8 weeks of treatment, the mice were euthanized, and bone mineral density (BMD), skeletal mechanical properties, bone histology, bone turnover biomarkers, serum levels of Dkk1 and sclerostin, muscle properties, and activity of the Wnt signaling were evaluated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;After 8 weeks of treatment, serum Dkk1 levels were lower in Dkk1-mAb and sequential groups than placebo group (&lt;em&gt;P&lt;/em&gt; &lt; 0.001, &lt;em&gt;P&lt;/em&gt; &lt; 0.05). L1-5 BMD was higher in Dkk1-mAb, alendronate, and sequential groups by 11.9 %, 22.8 %, and 23.1 % than placebo group (&lt;em&gt;P&lt;/em&gt; &lt; 0.05 or &lt;em&gt;P&lt;/em&gt; &lt; 0.001), with BMD at left femur increased by 12.8 % and 21.0 % in alendronate and sequential groups than placebo group (&lt;em&gt;P&lt;/em&gt; &lt; 0.05 or &lt;em&gt;P&lt;/em&gt; &lt; 0.001). The sequential group exhibited higher vertebral trabecular volume/total volume (39.9 %), bone surface/total volume (25.8 %), trabecular BMD (4.0 %), and trabecular thickness (13.1 %) than Dkk1-mAb group (&lt;em&gt;P&lt;/em&gt; &lt; 0.01 or &lt;em&gt;P&lt;/em&gt; &lt; 0.001), and higher cortical BMD, thickness than Dkk1-mAb (2.9 %, &lt;em&gt;P&lt;/em&gt; &lt; 0.01; 6.6 %, &lt;em&gt;P&lt;/em&gt; &lt; 0.05) and alendronate (2.2 %, 5.7 %, all &lt;em&gt;P&lt;/em&gt; &lt; 0.05) groups. All treatment groups showed greater bone strength, cross-sectional area of muscle, and grip strength than placebo group. The expression of &lt;em&gt;Lef1&lt;/em&gt; was significantly increased in bones of Dkk1-mAb and sequential groups. No pathological abnormalities in vital organs were found in all groups, suggesting that Dkk1-mAb had a good safety profile.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The novel Dkk1-mAb has therapeutic potential in osteoporosis, which can increase BMD and bone strength, improve bone microarchitecture and muscle performance of orchiectomy-induced osteoporotic mice through activating the WNT pathway, and its sequential treatment with alendronate achieves additive benefits.&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 study found that the novel Dkk1-mAb can increase BMD and bone strength, improve bone microarchitecture and muscle performance of orchiectomy-induced osteoporosis mice, and sequential treatment with Dkk1-mAb and alendronate ach","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101022"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419920","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 prevalence, incidence, and years lived with disability (YLDs) of osteoarthritis: trends from 1990 to 2021 and projections to 2050","authors":"Mingjue Chen ,&nbsp;Sheng Chen ,&nbsp;Chao Xie ,&nbsp;Feiyun Li ,&nbsp;Chu Tao ,&nbsp;Weiyuan Gong ,&nbsp;Minghao Qu ,&nbsp;Sixiong Lin ,&nbsp;Zengwu Shao ,&nbsp;Guozhi Xiao","doi":"10.1016/j.jot.2025.11.005","DOIUrl":"10.1016/j.jot.2025.11.005","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;To comprehensively assess the global burden of osteoarthritis (OA) from 1990 to 2021, analyze trends and patterns in its epidemiological shifts, and to project its changes through 2050.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Data were extracted from the Global Burden of Disease Study 2021, including the numbers and age-standardized rates (ASRs) of prevalence, incidence, and years lived with disability (YLDs) of OA. We described OA epidemiology and trends by sex, age, anatomic site, high body mass index (BMI), sociodemographic index (SDI), and geographic regions, using estimated annual percentage changes (EAPCs), joinpoint regression analysis, and Age-period-cohort (APC) analysis. The OA burden was decomposed into contributions from aging, population size, and epidemiologic changes, and the changes of OA burden through 2050 were predicted by Bayesian APC (BAPC) model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;GBD 2021 estimated 607.0 million prevalent cases, 46.6 million incident cases, and 21.3 million YLDs of OA in 2021, with a globally increasing trend in overall burden observed from 1990 to 2021. The number of YLDs cases attributable to high BMI increased threefold, from 1.45 million in 1990 to 4.42 million in 2021. Joinpoint regression analysis indicated that the most pronounced increases were observed during 2006–2009 for prevalence, 2000–2009 for incidence, and 2006–2009 for YLDs. The risk of OA prevalence, incidence, and YLDs were influenced by age, period and cohort effect. Regarding the age effect, the relative risks for these outcomes initially increased and then declined. For the period effect, the relative risks increased by approximately 1.7-, 1.2-, and 1.7-fold for these outcomes. In the cohort effect, earlier-born cohorts demonstrated higher risks than their later-born counterparts. Results revealed that female individuals, knee OA, and middle SDI quintile were responsible for the most significant prevalence. The primary drivers of these changes were population growth and aging. Notably, the OA burden globally was predicted to increase from 2022 to 2050, with predicted values of 1.2 billion prevalent cases, 77.8 million incident cases, and 41.6 million YLDs by 2050.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;As a major global health issue, OA demonstrated a steady rise in global burden between 1990 and 2021, highlighting the pressing need for improved OA management strategies. This study offers valuable insights for policymakers in optimizing healthcare resource distribution and designs targeted interventions.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;OA is a highly prevalent musculoskeletal disorder worldwide, with a globally increasing trend in its overall burden, imposing significant medical and economic challenges on both societies and individuals. Therefore, timely updates and comprehensive analyses of OA epidemiological data are crucial for the public, researchers, and healthc","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101029"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419913","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":"Pathomechanism of LYPD6 enhancing abnormal hyperostosis via Wnt/β-catenin signaling pathway in diffuse idiopathic skeletal hyperostosis","authors":"Sinian Wang,&nbsp;Xiaojiang Pu,&nbsp;Qingshuang Zhou,&nbsp;Haojie Chen,&nbsp;Zhuang Qian,&nbsp;Zhenhua Feng,&nbsp;Zezhang Zhu,&nbsp;Bin Wang,&nbsp;Yong Qiu,&nbsp;Xu Sun","doi":"10.1016/j.jot.2025.10.003","DOIUrl":"10.1016/j.jot.2025.10.003","url":null,"abstract":"<div><h3>Background</h3><div>Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory metabolic bone disorder marked by progressive ectopic ossification at spinal and peripheral entheses. Its molecular etiology is poorly understood. We investigated whether Ly6/uPAR domain–containing 6 (LYPD6) regulates osteoblast differentiation and drives pathological hyperostosis in DISH.</div></div><div><h3>Methods</h3><div>Primary osteoblasts from DISH patients and matched controls were assessed for ALP activity, calcium deposition, and expression of osteogenic markers. RNA sequencing identified LYPD6 as a candidate; its expression was validated by qRT-PCR, Western blot, and immunofluorescence. siRNA-mediated knockdown and lentiviral overexpression of LYPD6 were performed in patient osteoblasts and MC3T3-E1 cells. A global LYPD6 knockout mouse model underwent micro-CT, femoral fracture healing assays, and biomechanical testing. Mechanistic studies evaluated LRP6 phosphorylation, β-catenin stabilization and nuclear translocation, and in silico docking of LYPD6 to LRP6.</div></div><div><h3>Results</h3><div>DISH osteoblasts displayed increased ALP activity, mineralization, and upregulated Runx2, OPN, Col1a1, BSP II, and Osterix. LYPD6 was among the top upregulated genes and confirmed at mRNA and protein levels. LYPD6 knockdown impaired mineralization and osteogenic marker expression, whereas overexpression enhanced them. LYPD6−/− mice exhibited reduced trabecular and cortical bone mass, delayed fracture healing, and weaker biomechanical properties. At the molecular level, LYPD6 promoted LRP6 phosphorylation, stabilized β-catenin, and increased its nuclear localization; docking data predict direct LYPD6–LRP6 binding.</div></div><div><h3>Conclusion</h3><div>Aberrant upregulation of LYPD6 drives pathological hyperostosis in DISH via activation of the canonical Wnt/β-catenin pathway.</div></div><div><h3>The translational potential of this article</h3><div>LYPD6 may serve as both a biomarker for DISH and a pharmacological target. Modulating its activity could inform future therapies: transient inhibition of LYPD6 might prevent or attenuate ectopic ossification in DISH and related hyperostotic disorders, whereas short-term activation could enhance bone repair in osteoporotic or nonunion fracture settings.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101011"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419914","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":"Extracellular vesicles originating from induced pluripotent stem cell-derived chondrocytes facilitate the regeneration of osteoarthritic cartilage","authors":"Yaqian Hu ,&nbsp;Pengzhen Cheng ,&nbsp;Liyuan Jia ,&nbsp;Xue Hao ,&nbsp;Guangyu Ding ,&nbsp;Meige Han ,&nbsp;Jing Fan ,&nbsp;Weiguang Lu ,&nbsp;Chuxin Zhou ,&nbsp;Zhuojing Luo ,&nbsp;Liu Yang","doi":"10.1016/j.jot.2025.101035","DOIUrl":"10.1016/j.jot.2025.101035","url":null,"abstract":"<div><h3>Background</h3><div>Articular cartilage, a highly specialized avascular connective tissue, forms a smooth, load-bearing surface on articulating bone ends to facilitate frictionless joint movement. While cell-derived small extracellular vesicles (sEVs) have emerged as promising therapeutic biomaterials for cartilage regeneration, two major limitations impede their clinical translation: the scarcity of autologous donor cells, and suboptimal functional efficacy of conventional sEVs preparations.</div></div><div><h3>Methods</h3><div>We established an induced pluripotent stem cell (iPSC)-based approach by differentiating iPSCs into chondrocytes (designated iChondrocytes). After characterizing the derived iChondrocytes, we isolated their secreted sEVs (iChondrocyte-sEVs) and systematically evaluated their therapeutic effects and underlying mechanisms in cartilage regeneration through <em>in vitro</em> and <em>in vivo</em> experiments.</div></div><div><h3>Results</h3><div>Functional assays revealed that iChondrocyte-sEVs significantly enhanced chondrogenic differentiation, stimulated extracellular matrix (ECM) deposition, and maintained chondrocyte homeostasis. In murine osteoarthritis (OA) models, intra-articularly administered iChondrocyte-sEVs efficiently penetrated deep cartilage layers, alleviated OA-associated pathological changes, and restored cartilage microstructure and biomechanical properties to near-normal levels. Furthermore, therapeutic intervention with iChondrocyte-sEVs resulted in significant improvements in joint mobility and motor function in OA-affected mice. Proteomic profiling identified serine racemase (SRR) as a key upregulated protein in iChondrocyte-sEVs. Mechanistic studies suggested that SRR may contribute to cartilage regeneration by suppressing the P38/ERK signaling pathway.</div></div><div><h3>Conclusions</h3><div>This study highlights the significant therapeutic potential of iChondrocyte-sEVs, demonstrating their ability to promote both structural and functional regeneration of articular cartilage. These findings suggest a promising novel strategy for OA treatment.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the therapeutic potential of iChondrocyte-sEVs, demonstrating their ability to promote both structural and functional regeneration of articular cartilage. These findings indicate a clinical conversion potential for OA treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101035"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419916","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":"Functional biomaterials for the treatment of periprosthetic joint infection: A systematic review of preclinical animal studies","authors":"Yejin Zhang ,&nbsp;Baoqi Li ,&nbsp;Chaoran Liu ,&nbsp;Tao Huang ,&nbsp;Markus Rupp ,&nbsp;Christoph Brochhausen ,&nbsp;Ning Zhang ,&nbsp;Wing Hoi Cheung ,&nbsp;Sharon Shui Yee Leung ,&nbsp;Ling Qin ,&nbsp;Hon Fai Chan ,&nbsp;Ronald Man Yeung Wong","doi":"10.1016/j.jot.2026.101047","DOIUrl":"10.1016/j.jot.2026.101047","url":null,"abstract":"<div><h3>Background</h3><div>Periprosthetic joint infection (PJI) is a serious complication following joint arthroplasty, often leading to implant failure, bone destruction, and high revision rates. Conventional treatments are limited by biofilm persistence and collateral tissue damage. Functional biomaterials, defined as materials with active therapeutic properties such as antimicrobial delivery, biofilm disruption, tissue regeneration, or immunomodulation, offer promising alternatives. This systematic review aims to evaluate the current landscape of functional biomaterials in preclinical PJI models and identify translational challenges.</div></div><div><h3>Methods</h3><div>A systematic search of PubMed, Web of Science, and Embase was conducted for studies published between January 2000 and April 2025. Inclusion criteria were preclinical studies using validated animal models of PJI and investigating biomaterials with at least one active therapeutic function. Studies without prosthetic joint components or lacking in vivo data were excluded. Two reviewers independently screened and extracted data, and risk of bias was assessed using SYRCLE's tool.</div></div><div><h3>Results</h3><div>23 studies met the inclusion criteria, covering a range of biomaterial platforms including polymer-based systems, metal-based materials, cement and inorganic materials, nanomaterials, and hydrogels. These materials demonstrated diverse mechanisms and delivery strategies, such as localized antibiotic release and biofilm disruption. However, limitations persist in model standardization, mechanistic validation, and translational feasibility.</div></div><div><h3>Conclusion</h3><div>Functional biomaterials show promise in enhancing PJI treatment outcomes. Future research should focus on developing multifunctional platforms with spatiotemporal control and robust evaluation in clinically relevant models.</div></div><div><h3>The translational potential of this article</h3><div>This review provides a strategic framework for guiding the design of next-generation biomaterials with integrated therapeutic functions, supporting the development of clinically viable solutions for PJI management.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101047"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419519","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}