Journal of Orthopaedic Translation最新文献

{"title":"A scaffold-free cartilage construct fabricated using a bio 3D printer accelerates critical-size bone defect regeneration","authors":"Hiromu Yoshizato , Daiki Murata , Shohei Kashimoto , Toshihiro Nonaka , Ryota Fujimoto , Yukiko Nagaishi , Manabu Itoh , Tadatsugu Morimoto , Koichi Nakayama","doi":"10.1016/j.jot.2025.101033","DOIUrl":"10.1016/j.jot.2025.101033","url":null,"abstract":"<div><h3>Background</h3><div>Critical-size bone defects (CSD), often resulting from trauma or tumour resection, represent a challenging clinical condition that is difficult to treat. Although autologous bone grafting is a common treatment, limitations such as donor site morbidity necessitate the development of novel therapeutic strategies. Approaches that mimic endochondral ossification, the natural process of bone development and healing, are increasingly recognised for their bone regenerative potential. The combination of mesenchymal stem cells and scaffolds, used in many bone regeneration studies, has drawbacks, such as scaffold-derived complications including chronic inflammation and fibrosis. To overcome these issues, we used a bio-three-dimensional (3D) printer that enables the fabrication of scaffold-free 3D cellular constructs. This study aimed to establish a novel therapeutic strategy for CSD by generating scaffold-free cartilage constructs from rat adipose tissue-derived mesenchymal stromal cells (rAT-MSCs) and evaluating their regenerative potential.</div></div><div><h3>Materials and methods</h3><div>Scaffold-free cellular constructs were fabricated using rAT-MSCs. Cartilage constructs were generated by chondrogenic induction. A 5-mm CSD was created in the diaphysis of the rat femur. Three experimental groups were established: a Defect group (n = 9), in which no material was implanted into the defect; an MSC group (n = 9), in which undifferentiated constructs were implanted into the defect; and an MSC-Ch (AT-MSC-derived chondrocyte) group (n = 9), in which cartilage constructs were implanted into the defect. Computed tomography (CT) and histological analyses were performed at 6 and 12 weeks post-implantation.</div></div><div><h3>Results</h3><div>CT scans showed significantly higher bone volume/total volume ratios in the MSC-Ch group than in the Defect and MSC groups at 6 and 12 weeks (<em>p</em> < 0.01). Histologically, the MSC-Ch group exhibited robust formation of new cortical and cancellous bone, continuous with native bone margins, leading to bone bridging. In contrast, the Defect and MSC groups demonstrated new bone formation confined to the periphery of the defect, with the central regions predominantly occupied by adipose and fibrous tissues. Histological scoring supported these findings, with the MSC-Ch group achieving significantly higher scores than the Defect and MSC groups at both time points (<em>p</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>Implantation of scaffold-free cartilage constructs derived from rAT-MSCs effectively promoted CSD healing. To the best of our knowledge, this is the first study to successfully regenerate a long bone CSD using AT-MSCs as the cell source by mimicking the endochondral ossification pathway. However, further studies using larger animal models are required to validate and translate these findings.</div></div><div><h3>The translational potential of this article</h3><div>Fabri","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101033"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147377900","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":"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":"Silencing SFRP1 in bone mesenchymal stem cells alleviates pediatric B-ALL-driven bone loss by activating Wnt/β-catenin signaling","authors":"Mengxia Li ,&nbsp;Xu He ,&nbsp;Xingzhi Liu ,&nbsp;Mimi Chen ,&nbsp;Qian Sun ,&nbsp;Ronghui Yu ,&nbsp;Wendong Liu ,&nbsp;Qi Wang ,&nbsp;Guanghao Su ,&nbsp;Qin Shi ,&nbsp;Xiaodong Wang","doi":"10.1016/j.jot.2026.101071","DOIUrl":"10.1016/j.jot.2026.101071","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Bone loss is the most common skeletal complication of childhood acute lymphoblastic leukemia (ALL) and seriously affects the long-term survival quality of children. However, the mechanisms behind bone loss are complicated and need to be elucidated. This study seeks to examine the principal parameters influencing the osteogenic development of bone marrow mesenchymal stem cells (BMSCs) in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) experiencing bone loss, and to identify viable ways for alleviating bone loss.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Firstly, bone mass of adolescent B-ALL patients and mice were evaluated with aged-matched cohorts. Then, human BMSCs (hBMSCs) were isolated from pediatric B-ALL patients and characterized by Flow Cytometry Assay (FCA). ALP, ARS, Oil Red O and toluidine blue staining were used to evaluate the trilineage differentiation of hBMSCs. Integrated RNA-seq and proteomic analyses were employed to identify differentially target osteogenic regulators in B-ALL-derived hBMSCs. On the based that secreted frizzled-related protein 1 (SFRP1) was demonstrated to be a regulator on B-ALL BMSC osteogenesis, BMSC-targeted liposomal nanocarriers were engineered to encapsulate lentiviral particles carrying therapeutic shSFRP1 RNA and grafted with E7 peptide (shSFRP1@Lipo-E7), enabling cell-specific gene silencing in BMSCs. Subsequently, shSFRP1@Lipo-E7 was delivered into B-ALL mice by tail vein injection and bone quality were evaluated by mico-CT and histomorphometric analysis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Adolescent B-ALL patients exhibited significant vertebral bone loss, with 33.8% of patients affected. In B-ALL mice, BMD and newbone formation were markedly reduced, while osteoclast activity increased. An increased expression of SFRP1 was identified to impair osteogenesis of BMSCs from B-ALL patients. Consequently, a BMSC-targeted nanoplatform, E7 peptide-modified liposomes containing lentiviral shSFRP1 (shSFRP1@Lipo-E7) was constructed successfully. As anticipated, shSFRP1@Lipo-E7 effectively suppressed SFRP1 expression in trabecular osteoblasts and rescued B-ALL mice from bone loss, supported by significantly increasing BMD and improved trabecular structure. Both &lt;em&gt;in vitro&lt;/em&gt; and vivo studies evidenced that silencing of SFRP1 activated Wnt/β-catenin signaling to promote BMSC osteogenesis and bone formation in B-ALL mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;High SFRP1 expression in B-ALL BMSCs suppresses osteogenesis and contributes to bone loss in B-ALL cohorts by inhibiting Wnt/β-catenin signaling, which afford a potential translatable target to reprogram bone homeostasis and prevent bone fragility in ALL patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The Translational Potential of this Article&lt;/h3&gt;&lt;div&gt;Given the negative correlation between SFRP1 overexpression in BMSCs of pediatric B-ALL related bone mass loss, precisely targeting SFRP1 in MSCs for intervention holds prom","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101071"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147540217","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":"Insights into predicting residual plate bending in vivo using sensor-informed finite element models","authors":"Jiaqi Yang ,&nbsp;Ya Su ,&nbsp;Baosheng Yin","doi":"10.1016/j.jot.2026.101058","DOIUrl":"10.1016/j.jot.2026.101058","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101058"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951007","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":"Integrating mechanistic research and emerging technologies to advance clinical translation in orthopaedics","authors":"Qiuli Qi,&nbsp;Ling Qin","doi":"10.1016/j.jot.2026.101102","DOIUrl":"10.1016/j.jot.2026.101102","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101102"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951299","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":"Author's reply to the letters regarding “Preclinical validation of finite element models for predicting in vivo residual plate bending using continuous implant sensor data”","authors":"Dominic Mischler ,&nbsp;Manuela Ernst ,&nbsp;Peter Varga","doi":"10.1016/j.jot.2026.101060","DOIUrl":"10.1016/j.jot.2026.101060","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"57 ","pages":"Article 101060"},"PeriodicalIF":5.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951300","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}