Journal of Orthopaedic Translation最新文献

{"title":"Brain–bone axis dysregulation: Biological code underlying the bidirectional association between depression and musculoskeletal disorders","authors":"Yang Li ,&nbsp;Sonu Ng ,&nbsp;Keyu Kong ,&nbsp;Minghao Jin ,&nbsp;Wenxuan Fan ,&nbsp;Wenjie Zhou ,&nbsp;Zanjing Zhai ,&nbsp;Huiwu Li","doi":"10.1016/j.jot.2025.101044","DOIUrl":"10.1016/j.jot.2025.101044","url":null,"abstract":"<div><div>Depression and musculoskeletal disorders including osteoporosis (OP), fractures, osteoarthritis (OA) and rheumatoid arthritis (RA) exhibit significant bidirectional epidemiological and pathophysiological links. Rising depression prevalence (approximately 2.7 % annually) is accompanied by the high global burden of musculoskeletal disorders. Shared mechanisms center on the neuroimmune–inflammatory axis: Depression-associated inflammation (e.g., IL-6, TNF-α) promotes bone resorption, cartilage degradation, and RA disease activity, while autonomic/endocrine dysregulation increases fracture risk through increased norepinephrine (NE) and cortisol. Contributing factors include oxidative stress, gut dysbiosis, and sex hormone imbalances. Antidepressants show divergent skeletal effects: selective serotonin reuptake inhibitors (SSRIs) may reduce bone mineral density (BMD) and increase fracture risk, while serotonin-norepinephrine reuptake inhibitors (SNRIs) can improve OA symptoms. Depression significantly worsens orthopedic outcomes, leading to increased fracture risk, pain and disability, reduced treatment response. Integrated care approaches and novel neuroimmune targets offer potential for improved comorbidity management.</div></div><div><h3>The Translational Potential of this Article</h3><div>This review links depression with common orthopaedic disorders by synthesizing convergent neuro-immune-endocrine and metabolic pathways, and documents measurable skeletal deficits. These insights support immediate, low-cost actions: bidirectional screening, strengthened orthopaedics–psychiatry referral, and pragmatic combination care bundles. If implemented, this approach could reduce fracture risk, pain, and disability while improving recovery trajectories.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101044"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420405","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":"Intermittent intra-articular delivery of FGF8b enhances cartilage homeostasis and attenuates osteoarthritis progression","authors":"Xiuqin Peng ,&nbsp;Jiaming Han ,&nbsp;Yu Tian ,&nbsp;Xiaohong Li ,&nbsp;Xuanqi Zhang ,&nbsp;Song Li ,&nbsp;Jun Yang ,&nbsp;Liang Chen ,&nbsp;Siru Zhou ,&nbsp;Nan Su ,&nbsp;Xueqin Mao ,&nbsp;Bin Zhang ,&nbsp;Hangang Chen ,&nbsp;Jing Yang ,&nbsp;Min Jin ,&nbsp;Can Li ,&nbsp;Wanling Jiang ,&nbsp;Peng Liu ,&nbsp;Yangli Xie ,&nbsp;Liang Kuang ,&nbsp;Lin Chen","doi":"10.1016/j.jot.2025.101037","DOIUrl":"10.1016/j.jot.2025.101037","url":null,"abstract":"<div><h3>Objective</h3><div>Osteoarthritis (OA) is a chronic disease characterized by degeneration of articular cartilage, affecting over half a billion individuals globally. Current treatments such as non-steroidal anti-inflammatory drugs are effective in symptom relief, but lack the ability to modify OA progression. Fibroblast growth factor 8b (FGF8b) plays crucial roles in chondrogenesis and cartilage formation, suggesting its potential application in cartilage homeostasis maintenance. This study aims to investigate the effect of exogenous FGF8b on cartilage protection and OA progression, and explore the underlying mechanisms.</div></div><div><h3>Design</h3><div>Therapeutic effects of intra-articular FGF8b injections either once weekly or once every four weeks were evaluated in OA mouse models induced by destabilization of the medial meniscus (DMM) using histological analysis, X-ray imaging, micro-computed tomography (micro-CT), immunohistochemistry (IHC), and RNA sequencing of cartilage. Additionally, the therapeutic effects and underlying mechanisms of FGF8b on human cartilage and chondrocytes were further investigated using ex vivo OA models and in vitro assays.</div></div><div><h3>Results</h3><div>Once-weekly administration of FGF8b attenuated cartilage degradation while exacerbating osteophyte formation in a dose-dependent manner. Higher doses of FGF8b resulted in stronger cartilage-protective effects while increased osteophyte formation. Conversely, intermittent administration of FGF8b (once every four weeks) protected cartilage from degeneration without causing significant osteophyte formation. Mechanistically, FGF8b was found to help the maintenance of cartilage homeostasis by promoting anabolic metabolism and inhibiting catabolic metabolism in chondrocytes through activation of the FGFR3-PI3K-AKT signaling pathway.</div></div><div><h3>Conclusions</h3><div>Exogenous FGF8b attenuates articular cartilage degeneration by increasing anabolism and inhibiting catabolism, thereby presenting therapeutic potential for OA treatment.</div></div><div><h3>The translational potential of this article</h3><div>In this study, we demonstrate that intermittent administration of FGF8b protects articular cartilage from degeneration by increasing anabolic metabolism and inhibiting catabolic metabolism in cartilage, making it a promising disease-modifying agent for OA. Moreover, the findings offer valuable insights into optimizing the exposure regimens of FGFs to achieve safer and more effective OA treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101037"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419918","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":"Profibrotic macrophage-derived CXCL4 promotes pericyte-to-myofibroblast transition after spinal cord injury","authors":"Gang Li ,&nbsp;Le Wang ,&nbsp;Xiaoyu Wu ,&nbsp;Xiaolin Zeng ,&nbsp;Lingli Long ,&nbsp;Wenwu Zhang ,&nbsp;Jiewen Chen ,&nbsp;Di Zhang ,&nbsp;Xi Chen ,&nbsp;YiLong Deng ,&nbsp;XinZhi ,&nbsp;Yong Wan ,&nbsp;Xiang Li","doi":"10.1016/j.jot.2025.101032","DOIUrl":"10.1016/j.jot.2025.101032","url":null,"abstract":"<div><h3>Introduction</h3><div>Spinal cord injury (SCI) induces fibrotic scarring that impairs axonal regeneration. Pericytes contribute to scar formation via pericyte-to-myofibroblast transition (PMT), yet the mechanisms underlying PMT in SCI remain unclear. Although CXCL4, a pleiotropic chemokine, is implicated in various fibrotic disorders, its role in driving PMT post-SCI remains unexplored.</div></div><div><h3>Objectives</h3><div>To investigate whether CXCL4 drives PMT after SCI, elucidate its mechanisms, and assess its therapeutic potential.</div></div><div><h3>Methods</h3><div>scRNA-seq characterized cell-type dynamics and profibrotic signals in injured mouse spinal cords. <em>In vitro</em>, primary pericytes were exposed to exogenous CXCL4 or co-cultured with Spp1⁺Fn1⁺ macrophages. PMT was evaluated by RT-qPCR, Western blot, immunofluorescence, and flow cytometry. PI3K/Akt inhibition or CXCR3 knockdown dissected signaling pathways. <em>In vivo</em>, intrathecal injections of a CXCL4-neutralizing antibody or PI3K inhibitor were administered post-injury. Pericyte differentiation and fibrotic remodeling were assessed via immunostaining, Masson's trichrome staining, and gene expression profiling. Axonal regeneration and motor function were evaluated using CST tracing, serotonergic fiber labeling, Basso Mouse Scale scoring, and footprint analysis.</div></div><div><h3>Results</h3><div>PMT occurred post SCI, with Pdgfrβ⁺Acta2⁺ pericytes acting as major contributors. Spp1⁺Fn1⁺ macrophage subpopulation was identified as the main source of CXCL4, transcriptionally regulated by MAFB. CXCL4 levels were significantly upregulated post-injury, while pericytes in the lesion expressed its receptor, CXCR3. <em>In vitro</em>, exogenous CXCL4 induced PMT in pericytes via PI3K/Akt signaling. Co-culture experiments confirmed that Spp1⁺Fn1⁺ macrophages promoted pericyte transition through the CXCL4/CXCR3 axis. <em>In vivo</em>, blocking CXCL4 or PI3K suppressed PMT, reduced fibrotic scarring, enhanced axonal regeneration, and improved locomotor function in SCI mice.</div></div><div><h3>Conclusion</h3><div>Profibrotic macrophage-derived CXCL4 activates CXCR3/PI3K/Akt signaling in pericytes, driving their transition into scar-forming myofibroblasts after SCI. Blocking this axis mitigates fibrosis and enhances axonal regeneration and motor recovery.</div></div><div><h3>The translational potential of this article</h3><div>This study indicates that targeting the CXCL4-driven pericyte-to-myofibroblast transition to reduce fibrotic scar formation may provide an effective therapeutic strategy for enhancing axonal regeneration and functional recovery after SCI.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101032"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420091","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":"Organoids and organs-on-chips for accelerating R&D and clinical translation in Orthopaedics: Emerging opportunities and regulatory pathways","authors":"Yiting Lei ,&nbsp;Yuwei Zhang ,&nbsp;Liangbin Zhou ,&nbsp;Zhilong Zhou ,&nbsp;Mario Rothbauer ,&nbsp;Long Bai ,&nbsp;Jiankun Xu ,&nbsp;Denghui Xie ,&nbsp;Ali Mobasheri ,&nbsp;Xin Zhang ,&nbsp;Dongquan Shi ,&nbsp;Changhai Ding ,&nbsp;Jiake Xu ,&nbsp;Wei Huang ,&nbsp;Shiqing Feng ,&nbsp;Liu Yang ,&nbsp;Yuxiao Lai ,&nbsp;Guanghua Lei ,&nbsp;Zhuojing Luo ,&nbsp;Chenzhong Li ,&nbsp;Zhong Alan Li","doi":"10.1016/j.jot.2025.10.013","DOIUrl":"10.1016/j.jot.2025.10.013","url":null,"abstract":"<div><div>While conventional <em>in vitro</em> and <em>in vivo</em> models of orthopaedic conditions have yielded valuable insights into disease mechanisms and drug efficacy, only a few discoveries have been successfully translated to clinical practice. Organoids and organs-on-chips (OoCs) are transforming orthopaedic translation by providing 3D customizable models that aim to faithfully recapitulate musculoskeletal (MSK) (patho)physiology. Using joint-mimicking OoCs and skeletal muscle organoids as examples, we review the evolution of these systems that have been developed to model the pathogenesis, progression, prognosis, and treatment of orthopaedic conditions. We highlight how organoid and OoC models recapitulate multi-tissue crosstalk, drug responses, and disease heterogeneity. Furthermore, we summarize and discuss the global regulatory landscape for organoids and OoCs. Current global regulatory trends support the potential of these human-centric platforms as alternatives, or even future replacements for animal testing. Looking ahead, organoids and OoCs are gaining increasing attention in AI-guided drug development, patient stratification, and regenerative medicine evaluation. The ongoing rapid developments are expected to position organoids and OoCs at the forefront of precision orthopaedics.</div></div><div><h3>The translational potential of this article</h3><div>This article accelerates the clinical translation of orthopaedic discoveries by demonstrating how OoCs and organoids can be positioned as regulatory-ready alternatives to animal studies. Using joint-on-a-chip systems and skeletal muscle organoid as examples, we review the technological development of these platforms. By connecting recent policy shifts from key global regulators, including the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), China National Medical Products Administration (NMPA), and Pharmaceuticals and Medical Devices Agency (PMDA), to practical model qualification steps, we provide clinicians, industry, and regulators with a clear pathway to adopt OoCs and organoids. This process will facilitate their use as human-centric systems for patient stratification, implant safety evaluation, and disease-modifying drug development within the 3Rs (Replacement, Reduction, and Refinement) framework.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101021"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420119","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":"USP39 inhibits MLKL phosphorylation and deubiquitination to suppress necroptosis of nucleus pulposus cells and attenuate intervertebral disc degeneration","authors":"Zhenyu Zhu ,&nbsp;Xiaofeng Lin ,&nbsp;Fanqi Kong ,&nbsp;Ziran Wang ,&nbsp;Yongcheng Liang ,&nbsp;Chenglong Ji ,&nbsp;Hongxuan Chen ,&nbsp;Kaiqiang Sun ,&nbsp;Changnan Wang ,&nbsp;Ximing Xu ,&nbsp;Jiangang Shi","doi":"10.1016/j.jot.2025.101039","DOIUrl":"10.1016/j.jot.2025.101039","url":null,"abstract":"<div><h3>Background</h3><div>Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain. Programmed cell death, particularly necroptosis, contributes to nucleus pulposus (NP) cell loss. Mixed lineage kinase domain-like protein (MLKL) phosphorylation plays a critical role in necroptotic execution, but its upstream regulation in IVDD remains poorly defined.</div></div><div><h3>Methods</h3><div>We analyzed human and mouse degenerative disc tissues, as well as TNF-α/Smac mimetic/Z-VAD-FMK (TSZ)-treated NP cells, to assess MLKL phosphorylation. MLKL knockdown in human NP cells and conditional knockout (CKO) in mice were performed to determine its functional role. Immunoprecipitation coupled with mass spectrometry identified potential MLKL-binding proteins. Functional assays with USP39 knockdown/overexpression, together with in vitro and in vivo IVDD models, were conducted to explore regulatory mechanisms.</div></div><div><h3>Results</h3><div>MLKL phosphorylation was markedly elevated in human IVDD tissues, LSI-induced mouse discs, and TSZ-stimulated NP cells. Genetic knockdown or conditional deletion of Mlkl significantly preserved extracellular matrix integrity and delayed degeneration. USP39 was identified as a novel MLKL-interacting deubiquitinase. USP39 expression was reduced in IVDD, and its overexpression inhibited MLKL ubiquitination and phosphorylation, alleviating NP cell degeneration. In vivo, AAV-mediated Usp39 delivery attenuated disc degeneration and suppressed MLKL activation.</div></div><div><h3>Conclusion</h3><div>Our study reveals that MLKL phosphorylation drives necroptosis in IVDD and identifies USP39 as a critical upstream regulator that deubiquitinates MLKL. Targeting the USP39-MLKL axis provides a promising therapeutic strategy for delaying IVDD progression.</div></div><div><h3>The Translational Potential of this Article</h3><div>This study reveals that USP39 inhibits MLKL phosphorylation through deubiquitination, thereby suppressing necroptosis of nucleus pulposus cells and alleviating IVDD. Targeting the USP39–MLKL axis provides a potential therapeutic strategy to preserve NP cell viability and slow the progression of IVDD, offering new insight for translational interventions in chronic low back pain.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101039"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419919","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":"Modular de- and re-construction of vascularized osteochondral tissues in an Organ-on-Chip dual-compartment platform","authors":"Andrea Mainardi ,&nbsp;Andrea Barbero ,&nbsp;Martin Ehrbar ,&nbsp;Marco Rasponi ,&nbsp;Ivan Martin ,&nbsp;Paola Occhetta","doi":"10.1016/j.jot.2025.10.009","DOIUrl":"10.1016/j.jot.2025.10.009","url":null,"abstract":"<div><h3>Background</h3><div>Homeostasis at the cartilage–bone interface of articular joints depends on tightly orchestrated signalling among chondrocytes, osteogenic progenitors, and subchondral vasculature. Disruption of this crosstalk is considered one of the main drivers of osteoarthritis (OA), the most prevalent musculoskeletal disease worldwide. However, the timing, location, and mechanisms underlying the pathological onset of OA remain unclear, hindering the development of targeted regenerative strategies. This knowledge gap emphasises the need for <em>in vitro</em> models that replicate OA's multi-tissue crosstalk in a representative yet accessible format.</div></div><div><h3>Methods and results</h3><div>Here, we present a modular, dual-compartment Organ-on-Chip (OoC) platform that enables the stepwise ‘de- and re-construction’ of the vascularized osteochondral unit, allowing systematic interrogation of cell-specific roles in homeostasis and inflammation. Through the side-by-side culture of human articular chondrocytes (hACs) and bone marrow-derived mesenchymal stromal cells (bmMSCs), we generated biphasic, compartmentalized constructs with a contiguous interface, in which bmMSCs exhibited osteogenic commitment without compromising the stable chondrogenic capacity of hACs. The addition of human umbilical vein endothelial cells (HUVECs) to the bmMSCs compartment at a finely tuned 3:2 ratio (bmMSCs:HUVECs) enabled the formation of lumenized vascular vessels surrounded by α-SMA–expressing cells and laminin sheaths, while preserving bmMSCs' osteogenic commitment. Under homeostatic conditions, the presence of a cartilage layer adjacent to such vascularized and mineralized tissue impeded vascular and stromal invasion, whereas exposure to IL-1β (1 ng/mL) allowed to override such chondrocyte “barrier,” triggering endothelial and stromal penetration into the cartilage, thus mimicking inflammatory OA.</div></div><div><h3>Conclusion</h3><div>The proposed platform combines ease of use, real-time imaging capabilities, and precise control over cellular modules, offering a versatile tool for future mechanistic studies in OA and related joint disorders.</div></div><div><h3>The translational potential of this article</h3><div>This modular Organ-on-Chip platform offers a physiologically relevant and experimentally accessible model of the vascularized osteochondral interface, enabling systematic dissection of cell-specific roles in joint homeostasis and inflammation. By recapitulating key features of early osteoarthritic pathology—including barrier breakdown, stromal invasion, and endothelial remodeling— with a highly modular and technologically robust approach, this system holds translational promise for preclinical testing of disease-modifying OA therapies, biomarker discovery, and regenerative strategies targeting cartilage–bone crosstalk.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101017"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420093","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":"Decellularized extracellular matrix restores Fibronectin/Integrin β1 balance through extracellular vesicles to rejuvenate chondrocytes and alleviate osteoarthritis progression","authors":"Aoyuan Fan ,&nbsp;Zhiying Pang ,&nbsp;Zheng Liu ,&nbsp;Feng Yin ,&nbsp;Yiming Wang","doi":"10.1016/j.jot.2025.10.011","DOIUrl":"10.1016/j.jot.2025.10.011","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Osteoarthritis (OA) is a prevalent degenerative joint disease driven largely by chondrocyte senescence. Extracellular vesicle (EV)-based therapies have emerged as a promising strategy; however, the extensive stem-cell expansion required to obtain therapeutic EV doses unavoidably erodes their potency.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;Leveraging our prior finding that decellularized extracellular matrix (dECM) rejuvenates stem cells during in vitro expansion, we further investigate whether dECM could resolve the current bottleneck in EV therapy by preserving therapeutic efficacy even in late-passage cells.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Human adipose-derived stromal cells (hADSCs) were expanded to passage 15 on either tissue culture plastic (TCP) or dECM, and their EVs were isolated. We first interrogated the capacity of dECM-primed EVs to counteract chondrocyte senescence and ER stress in vitro, then validated their therapeutic impact in a rat OA model. Mechanistic insight was pursued through proteomic profiling, followed by loss- and gain-of-function studies using pharmacologic inhibitors and targeted knockdown.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Late-passage EVs generated under dECM (dECM-P15-EVs) surpassed those under TCP (TCP-P15-EVs) in alleviating chondrocyte senescence and ER stress. In vivo, dECM-P15-EVs attenuated cartilage degradation more effectively than their conventionally cultured counterparts. Proteomics revealed dECM-P15-EVs were enriched in both FN and its receptor integrin β1 (ITGB1). Either pharmacologic blockade or siRNA-mediated knockdown of FN in dECM or of ITGB1 in EV-producing cells abrogated the anti-senescence and chondro-protective benefits of dECM-P15-EVs. Further experiments implicated FN/ITGB1 transfer as a critical step in re-activating downstream SIRT1 signaling.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;By reinstating FN/ITGB1 homeostasis and reinvigorating SIRT1-dependent pathways, dECM-P15-EVs effectively counteract chondrocyte senescence and OA progression—offering a scalable, senescence-resistant platform for next-generation EV therapy.&lt;/div&gt;&lt;div&gt;The Translational Potential of this Article: Producing the large quantities of EVs required for clinical OA therapy necessitates prolonged expansion of stem cells, which inevitably blunts EV efficacy. dECM culture restores the potency of EVs without additional biosafety concerns. Thus, dECM-P15-EVs offer strong translational promise as an advanced, EV-centric OA therapy that overcomes current limitations.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;Producing the large quantities of EVs required for clinical OA therapy necessitates prolonged expansion of stem cells, which inevitably blunts EV efficacy. dECM culture restores the potency of EVs without additional biosafety concerns. Thus, dECM-P15-EVs offer strong translational promise as an advanced, EV-centric OA therapy that overcomes current lim","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101019"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420118","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":"VEGF-neutralized platelet-rich plasma with adipose-derived stromal vascular fraction enhanced osteochondral repair in a point-of-care goat model","authors":"Shinsuke Kihara ,&nbsp;Benjamin B. Rothrauff ,&nbsp;Tomoya Iseki ,&nbsp;Kalon J. Overholt ,&nbsp;Yijen L. Wu ,&nbsp;Hang Lin ,&nbsp;Peter G. Alexander ,&nbsp;Rocky S. Tuan","doi":"10.1016/j.jot.2025.101034","DOIUrl":"10.1016/j.jot.2025.101034","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background/objective&lt;/h3&gt;&lt;div&gt;Focal articular cartilage defects do not heal spontaneously. Platelet-rich plasma (PRP) is as an autologous source of growth factors that has been reported to promote tissue healing. However, PRP contains angiogenic factors such as vascular endothelial growth factor (VEGF) that are known to inhibit chondrogenesis and promote osteoarthritis progression. Mesenchymal stem cells (MSCs) have also shown promise in promoting focal cartilage repair, but MSC therapies typically require cell isolation and expansion before implantation in a second surgery. Adipose-derived stromal vascular fraction (SVF) is rich in MSCs and can be harvested and delivered in a single procedure. The purpose of this study was to determine the effect of VEGF-neutralized PRP on &lt;em&gt;in vitro&lt;/em&gt; chondrogenesis and &lt;em&gt;in vivo&lt;/em&gt; osteochondral repair when combined with an MSC-rich SVF in a single-stage point-of-care goat model. It was hypothesized that VEGF-neutralized PRP would enhance &lt;em&gt;in vitro&lt;/em&gt; chondrogenesis and improve &lt;em&gt;in vivo&lt;/em&gt; osteochondral repair when combined with SVF.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Adipose-derived MSCs (ASCs) were encapsulated in photocrosslinkable hydrogels supplemented with (1) Hanks’ Balanced Salt Solution (HBSS), (2) PRP, (3) VEGF-neutralized PRP, or (4) transforming growth factor- β3 (TGF-β3) for &lt;em&gt;in vitro&lt;/em&gt; experiments. Cell viability and gene expression were determined on days 3, 7, and 21. For &lt;em&gt;in vivo&lt;/em&gt; experiments, ASC-rich SVF was procured and delivered in the aforementioned hydrogels to an osteochondral defect in a single-stage point-of-care goat model. At 6 months, osteochondral regeneration was characterised by gross appearance, histological grading, immunohistochemistry, biomechanical testing, and quantitative MRI.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;&lt;em&gt;In vitro&lt;/em&gt; cell viability remained high, with no differences across groups. TGF-β upregulated chrondrogenic, fibrogenic, and hypertrophic gene expression. VEGF-neutralized PRP, as compared to native PRP, preferentially upregulated chondrogenesis while inhibiting fibrogenesis. In the point-of-care &lt;em&gt;in vivo&lt;/em&gt; goat model, VEGF-neutralized PRP tended to best recapitulate native osteochondral macroscopic appearance, histology, immunohistochemical content, biomechanical properties (i.e., elastic modulus), and biochemical content on quantitative MRI, although results did not consistently reach statistical significance. By comparison, TGF-β upregulated hypertrophic markers with evidence of ectopic bone formation on histology, increased Collagen I and X on immunohistochemistry, supraphysiological elastic modulus, and overly dense biochemical content on quantitative MRI.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Neutralization of VEGF in PRP enhanced &lt;em&gt;in vitro&lt;/em&gt; chondrogenesis of adipose-derived MSCs and tended to best improve &lt;em&gt;in vivo&lt;/em&gt; osteochondral regeneration when combined with stromal vascular fraction","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101034"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420411","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":"CMTM6 promotes synovial proliferation and macrophage polarization by preventing ubiquitination of TAK1 in rheumatoid arthritis","authors":"Xiaomeng Luo ,&nbsp;Lingling Xu ,&nbsp;Juan Cai ,&nbsp;Siyang Ma ,&nbsp;Haining Song ,&nbsp;Pingting Yang ,&nbsp;Chunshu Yang","doi":"10.1016/j.jot.2025.09.009","DOIUrl":"10.1016/j.jot.2025.09.009","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and bone destruction. Abnormal TNF/TNFR signaling leads to various dysregulations in Fibroblast-like synoviocytes (FLSs), including proliferation, migration, and cytokine production. CKLF like MARVEL transmembrane domain containing 6 (CMTM6) plays a crucial role in tumor progression and immune escape. This study aimed to research the function of CMTM6 in fibroblast-like synoviocytes (FLSs) of rheumatoid arthritis (RA).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials and methods&lt;/h3&gt;&lt;div&gt;The level of CMTM6 in serum and synovial fluid was detected by enzyme-linked immunosorbent assays (ELISA). &lt;em&gt;CMTM6&lt;/em&gt; was silenced by transfecting FLSs with small interfering RNAs (siRNAs). Proliferation, migration, and apoptosis were assessed using a Cell counting kit-8 (CCK-8), Matrigel invasion assays and flow cytometry respectively. The levels of interleukin-1β (IL-1β) and interleukin-6 (IL-6) of cell culture supernatant were detectd with ELISA. The protein expression level of TNF/TNFR pathway and its downstream NF-κB/MAPK signaling were detected through RNA-sequencing and determined by western blotting (WB). Co-Immunoprecipitation, immunofluorescence and pymol analysis were used to confirm the interaction between CMTM6 and TGF-β-activated kinase 1 (TAK1). We used ubiquitination assay and Cycloheximide (CHX) assay to detect degradation of TAK1. The collagen II-induced arthritis (CIA) mouse model were established in DBA/1 mice and treated with &lt;em&gt;Cmtm6&lt;/em&gt; shRNA (AAV-sh&lt;em&gt;Cmtm6&lt;/em&gt;) or rAAV vector (AAV-Ctrl). Micro-CT and histological analyses evaluated the severity of arthritis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Increased levels of CMTM6 in the serum, synovial fluid and synovial tissues were observed in RA patients. Silencing &lt;em&gt;CMTM6&lt;/em&gt; suppressed proliferation, migration and inflammatory cytokines secretion and promote the apoptosis of FLSs. Mechanistically, CMTM6 maintains the stability of TAK1 by inhibiting its ubiquitin-proteasome degradation, leading to the activation of TNF/TNFR pathway and its downstream NF-κB/MAPK signaling. In addition, CMTM6 promoted the M1-macrophage polarization by producing more pro-inflammation cytokines in the micro-environment of joints. AAV-sh&lt;em&gt;Cmtm6&lt;/em&gt; treatment attenuated the severity of joint damage of CIA mice and reduced the Cmtm6/Tak1 expression similarly to TNF-α antibody.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;CMTM6 participates in the proliferation, migration, and apoptosis of FLSs and exacerbates joint inflammation. Mechanistically, CMTM6 activates the NF-κB/MAPK signaling pathway by protecting TAK1 from ubiquitination degradation.&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 shows that CMTM6 mediates inflammatory signatures such as proliferation and migration of FLSs through TAK1. Targeting CMTM6 may become a potential therapeutic target for RA.&lt;/div&gt;&lt;","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101005"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147419573","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":"Cell-based therapies for intervertebral disc degeneration: Navigating the path from promise to clinical reality","authors":"Lei Shi ,&nbsp;Lizhi Jiang ,&nbsp;Tong Xing ,&nbsp;Kexin Liu ,&nbsp;Chen Chen ,&nbsp;Peixiang Ma ,&nbsp;Tobias Winkler ,&nbsp;An Qin ,&nbsp;Jie Zhao","doi":"10.1016/j.jot.2025.101041","DOIUrl":"10.1016/j.jot.2025.101041","url":null,"abstract":"<div><div>Low back pain (LBP) remains a leading contributor to global health loss, with its disease burden escalating steadily worldwide. Intervertebral disc degeneration (IDD) serves as the primary pathological basis for specific forms of LBP, driven by a multifactorial cascade involving molecular, biochemical and structural alterations. Conventional conservative treatments merely mitigate symptoms without abrogating or reversing the degenerative process, while surgical interventions—though effective for relieving neural compression—fail to regenerate damaged disc tissue and carry inherent risks such as recurrence. In this context, cell-based therapies have emerged as a major focus of regenerative research for IDD, offering unique potential to facilitate tissue repair and ameliorate pain. Nevertheless, substantial hurdles endure: the mechanisms of action remain incompletely defined, standardized cell products are lacking, and robust evidence supporting long-term safety and efficacy is scarce. This review focuses on cell-based therapies for IDD, systematically examines the global research landscape and recent advances, investigates the proposed mechanisms of action, analyzes the current status of clinical research, and outlines future directions, aiming to inform and guide further exploration in this rapidly evolving field.</div><div><strong>The Translational Potential of this Article</strong>: This work systematically synthesizes current research landscape of cell-based therapies for IDD, elucidates key translational hurdles, and proposes actionable solutions, delivering critical guidance to accelerate the translation of cell-based therapies into clinical practice.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"56 ","pages":"Article 101041"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147420133","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}