Journal of Orthopaedic Translation最新文献

{"title":"Classification and pathoanatomy of posterior malleolus fracture based on posterior malleolus-associated ligaments and ankle stability","authors":"Yongqi Li , Yi Liao , Rui Luo , Tian Zhao , Shun Wang , Yunfeng Yang","doi":"10.1016/j.jot.2025.09.003","DOIUrl":"10.1016/j.jot.2025.09.003","url":null,"abstract":"<div><h3>Background</h3><div>The clinical significance of previous posterior malleolus fracture classifications is limited because they are mainly based on fracture morphology. On the basis of posterior malleolus-associated ligaments and ankle stability, injury mechanism, and fracture morphology, a novel posterior malleolus fracture classification system was proposed to clarify the pathoanatomy of posterior malleolus fracture and guide clinical diagnosis and treatment.</div></div><div><h3>Methods</h3><div>Twenty fresh frozen cadaver specimens of the lower limbs were collected, posterior malleolus-associated ligaments were dissected, and the range of their tibial insertion, average length, and direction were measured. Clinically,we retrospectively analyzed the imaging information of 296 patients with posterior malleolus fractures. Correlating the anatomical measurements of posterior malleolus-associated ligaments of fresh frozen cadaver specimens with the computed tomography(CT) imaging data of posterior malleolus fracture of clinical patients, a clinically practical classification system of posterior malleolus fracture was established. In addition, the novel classification was compared with Haraguci classification and Mason classification.</div></div><div><h3>Results</h3><div>Posterior malleolus-associated ligaments include the posterior inferior tibiofibular, inferior transverse tibiofibular, and posterior tibiotalar ligaments from the posterolateral to posteromedial tibia. A total of 296 posterior malleolus fractures were divided into three types. Type I posterior malleolus fracture involved only the tibial insertion of the inferior transverse tibiofibular ligament (36 cases, 12.2 %). Type Ⅱ posterior malleolus fracture involved the tibial insertions of the inferior transverse tibiofibular and posterior inferior tibiofibular ligaments and was divided into two subtypes according to whether or not articular cartilage or die-punch injury was present (ⅡA, 150 cases, 50.7 %; ⅡB, 79 cases, 26.7 %). Type Ⅲ posterior malleolus fracture involved all the tibial insertions of the inferior transverse tibiofibular, posterior inferior tibiofibular, and posterior tibiotalar ligaments and included two subtypes according to the fragment number of posterior malleolus fracture (ⅢA, 11 cases, 3.7 %; ⅢB, 20 cases, 6.8 %).</div></div><div><h3>Conclusions</h3><div>The formation of posterior malleolus fracture stems from the combined effects of external force and internal ligament structure. Correlating posterior malleolus-associated ligaments with the classification of posterior malleolus fracture is of great significance. The proposed classification system considers posterior malleolus-associated ligaments, injury mechanism, and fracture morphology and thus clarifies the pathoanatomy of posterior malleolus fracture and serves as a guide for clinical diagnosis and treatment.</div></div><div><h3>The translational potential of this article</h3><div>The clinical signifi","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 339-345"},"PeriodicalIF":5.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266660","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":"Epigenetic reprogramming via EZH2 inhibition rescues fibroadipose pathogenesis in secondary lymphedema through activating PPARγ signaling","authors":"Ziyu Chen ,&nbsp;Zhi Yao ,&nbsp;Mengfan Wu ,&nbsp;Yuluan Wu ,&nbsp;Jianlin Zhang ,&nbsp;Zhuangyao Liao ,&nbsp;Junyu Qian ,&nbsp;Jiewen Wei ,&nbsp;Lili Song ,&nbsp;Longbiao Yu ,&nbsp;Jingjing Wen ,&nbsp;Zhegang Zhou ,&nbsp;Yihao Wei ,&nbsp;Yuefeng Yao ,&nbsp;Zetao Ma ,&nbsp;Pei Liu ,&nbsp;Shailesh Agarwal ,&nbsp;Ye Li ,&nbsp;Lixiang Xue ,&nbsp;Deli Wang","doi":"10.1016/j.jot.2025.08.014","DOIUrl":"10.1016/j.jot.2025.08.014","url":null,"abstract":"<div><h3>Background</h3><div>Secondary lymphedema, a progressive disorder characterized by pathological fibroadipose tissue accumulation, is a common problem after cancer treatment and orthopedic surgery. It remains a therapeutic enigma due to its self-perpetuating fibrotic cascade and lack of disease-modifying therapies. While current therapeutic approaches focus on symptom management and volume reduction, they don't address the epigenetic reprogramming driving fibrotic commitment—a process recently linked to enhancer of zeste homolog 2 (EZH2). Although EZH2 inhibitor EPZ6438 has been approved for clinical application, its therapeutic potential in fibroadipose pathogenesis remains unexplored, leaving a critical gap in understanding epigenetic factors in lymphedema progression.</div></div><div><h3>Methods</h3><div>Human skin tissue was collected from lymphedema patients and normal controls. Histological/immunofluorescence staining and RNA sequencing were performed. In vivo, a mouse hind limb secondary lymphedema model was established by lymphadenectomy. EZH2 inhibitors (EPZ6438, GSK126) were intraperitoneally injected. Skin samples were collected for histological assessment and immuno-staining. In vitro, adipose-derived mesenchymal stem cells (AdMSCs) were treated with transforming growth factor beta 1 (TGFβ1) and EZH2 inhibitors. Western blot, RT-qPCR and ChIP-qPCR were carried out.</div></div><div><h3>Results</h3><div>Fibrous tissue was observed in lymphedema samples, with concomitant elevation of EZH2 and H3K27me3 levels in the nucleus. RNA sequencing and gene set enrichment analysis (GSEA) revealed significant downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling in lymphedema tissue. Pharmacological inhibition of EZH2 significantly attenuated cutaneous thickening, fibroadipose layer expansion, and collagen deposition in the mouse lymphedema model. PPARγ was induced while phospho-SMAD2/3 activation was suppressed. In TGFβ1 stimulated AdMSCs, EZH2 inhibition upregulated PPARγ expression and inhibited fibrogenic differentiation of the cells.</div></div><div><h3>Conclusion</h3><div>EZH2 inhibitors exerted potent anti-fibrotic effects in secondary lymphedema though activating PPARγ signaling, offering novel insights and strategies for fibrotic disorders.</div></div><div><h3>The translational potential of this article</h3><div>This study demonstrated that targeted inhibition of the EZH2-PPARγ axis effectively inhibited fibrogenic differentiation of AdMSCs and reduced fibroadipose tissue in secondary lymphedema, indicating it is a promising strategy for secondary lymphedema treatment, offering novel insights and strategy for musculoskeletal fibrotic disorders.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 309-322"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220802","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":"Naringin inhibits the osteoblast-osteoclast pyroptosis cascade reaction mediated by accumulated bone marrow adipose tissue in the treatment of postmenopausal osteoporosis","authors":"Zhichao Li ,&nbsp;Kuanhui Gao ,&nbsp;Mengjie Wang ,&nbsp;Songlin Liang ,&nbsp;Dandan Li ,&nbsp;Peng Zhang ,&nbsp;Wenxiang Cheng ,&nbsp;Zhanwang Xu ,&nbsp;Nianhu Li","doi":"10.1016/j.jot.2025.09.004","DOIUrl":"10.1016/j.jot.2025.09.004","url":null,"abstract":"<div><h3>Background</h3><div>Excessive expansion of bone marrow adipose tissue (BMAT) is considered to be a crucial factor leading to postmenopausal osteoporosis (PMOP). Conventional osteoporosis drugs mainly focus on inhibiting bone resorption, promoting bone formation or calcium absorption, with less emphasis on regulating BM adiposity. Potential therapeutic agents need to be screened. The objective of this study is to explore the potential mechanisms by which naringin (NG), abundant in citrus fruits, regulates lipid metabolism and exerts bone-protective activities.</div></div><div><h3>Methods</h3><div>Key pathways and molecular mechanisms underlying NG's amelioration of PMOP symptoms in mice were investigated using RNA sequencing. Molecular docking and surface plasmon resonance were employed to identify the direct targets of NG. The roles of key molecules identified were validated in PMOP through <em>in vivo</em> overexpression or pharmacological inhibition.</div></div><div><h3>Results</h3><div>NG treatment improved ovariectomy-induced bone loss and reduced bone marrow fat accumulation. Correspondingly, the co-culture system of adipocytes/osteoblasts suggested impaired osteoblast functionality and alterations in mitochondrial dynamics, which was reversed by NG through its antioxidative effect to restore mitochondrial fission and fusion balance. Furthermore, RNA sequencing results revealed that adipocytes induced osteoblast pyroptosis mediated by NLRP3 inflammasomes. This osteoblast pyroptosis was alleviated following NG to clear ROS or target TLR2 to inhibit MyD88/NF-κB pathway activation. Subsequently, a strong M1 macrophage polarization tendency was observed, as well as accelerated early osteoclast differentiation induced by RANKL, in a co-culture system of pyroptosis-affected osteoblasts and macrophages. However, these changes were reversed by early NG in osteoblasts. Finally, anti-PMOP effect of NG was attenuated in PMOP mice with overexpressed NLRP3, and pharmacological inhibition of NLRP3 alleviated the PMOP symptoms.</div></div><div><h3>Conclusion</h3><div>NG can regulate osteoblast mitochondrial dynamics disorder through suppression of BMAT-mediated lipotoxicity, and can modulate the MyD88/NF-κB signaling pathway via direct targeting of TLR2, thereby inhibiting the adipocyte-osteoblast-osteoclast pyroptosis cascade.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the pivotal role of BMAT-triggered pyroptosis cascades in PMOP pathogenesis and demonstrates NG's therapeutic potential. Our findings position bone marrow adiposity modulation as a promising anti-PMOP strategy, emphasizing the importance of developing natural adiposity regulators like NG for targeted intervention.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 323-338"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220801","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":"Tirzepatide, a dual GLP-1 and GIP receptor agonist, promotes bone loss in obese mice via gut microbial-related metabolites","authors":"Ning Chen ,&nbsp;Mengdan Zhang ,&nbsp;Baohong Shi ,&nbsp;Xiumei Luo ,&nbsp;Rui Huang ,&nbsp;Zhengqiong Luo ,&nbsp;Junliang He ,&nbsp;Shengye Xue ,&nbsp;Na Li ,&nbsp;Zemin Ling ,&nbsp;Hao Guo ,&nbsp;Ren Xu ,&nbsp;Yuejun Liu","doi":"10.1016/j.jot.2025.09.002","DOIUrl":"10.1016/j.jot.2025.09.002","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;As a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, Tirzepatide (TZP) is a recently approved medication for treating type 2 diabetes mellitus (T2DM) and obesity; however, the effect of TZP in bone remodeling remains unclear.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;1. The effect of Tirzepatide on osteoblasts and osteoclasts was observed by inducing differentiation of bone marrow mesenchymal cells (BMSCs) &lt;em&gt;in vitro&lt;/em&gt;. 2. Db/db mice were used as a pathological model to investigate the role of TZP on bone metabolism. After TZP intervention, the feces in the intestinal tract of mice were collected for 16s rRNA gene sequencing to select the candidate gut microbiota most related to bone mass, and the effects of gut microbiota on bone metabolism were verified through subsequent microbiota supplementation experiments. 3. Metabolomics was used to analyze the difference of fecal metabolites between mice with the candidate microbiota supplement and those without, and the effect of candidate metabolites on bone metabolism was verified by the &lt;em&gt;in vitro&lt;/em&gt; intervention of differential metabolites in BMSCs induction differentiation experiments.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;We found that TZP intervention resulted in a significant decrease in bone mass accrual &lt;em&gt;in vivo&lt;/em&gt;. TZP was not indispensable to the differentiation of osteoblasts and osteoclasts &lt;em&gt;in vitro&lt;/em&gt;. Bone and fat homeostasis were modulated by gut microbiota. We further demonstrated that the biodiversity of the gut microbiota in db/db mice was strikingly altered after TZP treatment. &lt;em&gt;Lachnospiraceae&lt;/em&gt;, a key pro-osteogenic component of gut microbiota was significantly reduced. As a main metabolite of &lt;em&gt;Lachnospiraceae&lt;/em&gt;, evodiamine played a role in suppressing osteoclastogenesis &lt;em&gt;in vitro&lt;/em&gt;. Based on this, the transplantation of the &lt;em&gt;Lachnospiraceae&lt;/em&gt; effectively ameliorated bone loss that was seen in db/db mice due to TZP treatment.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;TZP administration leads to bone loss in the context of diabetes and obesity, and targeting the composition of gut microbiota may provide a potential way to protect bone health in type 2 diabetic patients treating with TZP.&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 indicates that TZP has a negative impact on bone mass, suggesting that clinical attention should be paid to the risk of further decline in bone mass after Tirzepatide treatment, and it is necessary to follow up on their bone metabolism. Additionally, the gut microbiota plays an important role in bone metabolism regulation, and supplementing with certain probiotics may have a preventive effect on bone mass reduction associated with TZP treatment. Our research provides a reference for the prevention and treatment of drug-related osteoporosis in patients with T2DM in the future.&lt;/div&gt;&lt;/di","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 280-292"},"PeriodicalIF":5.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220803","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":"Cuproptosis in osteoarthritis: Exploring chondrocyte cuproptosis and therapeutic avenues","authors":"Haotian Hua ,&nbsp;Feng Cheng ,&nbsp;Zhuo Meng ,&nbsp;Anqi Zhang ,&nbsp;Mengying Li ,&nbsp;Minjie Zhang ,&nbsp;Pengqiang Lou ,&nbsp;Yiwen Zhu ,&nbsp;Peijian Tong ,&nbsp;Yang Zhang","doi":"10.1016/j.jot.2025.09.006","DOIUrl":"10.1016/j.jot.2025.09.006","url":null,"abstract":"<div><h3>Background</h3><div>Cuproptosis, a newly identified form of cell death, presents an as-yet-unclear potential correlation with Osteoarthritis (OA) pathogenesis. This study aimed to explore the relationship between chondrocyte cuproptosis and OA, and to evaluate the therapeutic potential of the copper ion chelator tetrathiomolybdate (TTM) in OA treatment.</div></div><div><h3>Methods</h3><div>We collected clinical cartilage samples and animal specimens, employing Micro-CT, histopathological staining, immunohistochemistry, and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) to evaluate the potential occurrence of chondrocyte cuproptosis during OA progression. In <em>vitro</em>, we used elesclomol and copper sulfate to create a cuproptosis model in mouse chondrocytes. Techniques like ICP-MS, CCK-8, and others were used to explore the role of cuproptosis in OA development. To assess if TTM can mitigate chondrocyte cuproptosis and decelerate OA progression, various methods were applied at cellular and animal levels. Metabolomics predicted pathways for TTM's potential OA improvement. Molecular docking was employed to predict the intervention target of TTM. The impact of glutathione (GSH) on chondrocyte cuproptosis and OA development was studied using si-glutathione synthetase (si-GSS) plasmid knockdown and exogenous GSH supplements.</div></div><div><h3>Results</h3><div>Our findings indicate that in the process of OA, chondrocytes show an increase in copper ion content, metabolic disorders of the cartilage matrix, low expression of cuproptosis - related proteins lipoamide dehydrogenase (DLAT), dihydrolipoamide succinyltransferase (DLST), and ferredoxin 1 (FDX1), and high expression of the heat shock protein70 (HSP70). As the primary target of cuproptosis, mitochondria experience significant impacts on respiratory function and morphology during this process. TTM enhances chondrocytes resistance to cuproptosis by promoting GSH expression, thus ameliorating the OA phenotype.</div></div><div><h3>Conclusion</h3><div>Chondrocyte cuproptosis is integral to pathogenesis and progression of OA, and TTM has emerged as a novel and potentially valuable therapeutic strategy for the treatment of this disease.</div></div><div><h3>The translational potential of this article</h3><div>Chondrocyte cuproptosis plays a key role in the occurrence and development of knee osteoarthritis. The copper ion chelator (Tetrathiomolybdate) has been proved to be able to treat knee osteoarthritis by alleviating chondrocyte cuproptosis.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 293-308"},"PeriodicalIF":5.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220804","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":"Macropinocytosis fuels osteoclast differentiation in bone-related diseases","authors":"Mengqin Gu ,&nbsp;Linyu Xue ,&nbsp;Shidian Ran ,&nbsp;Ying Yuan ,&nbsp;Qiming Zhai ,&nbsp;Hongmei Zhang ,&nbsp;Hua Zhang ,&nbsp;Ping Ji","doi":"10.1016/j.jot.2025.09.005","DOIUrl":"10.1016/j.jot.2025.09.005","url":null,"abstract":"<div><h3>Objective</h3><div>Multinucleated osteoclasts are the principal specialised cells responsible for bone resorption, but osteoclastogenesis, the formation of osteoclasts, entails substantial nutrient and bioenergetic demands. Macropinocytosis is an efficient pathway for nutrient scavenging in metabolically active cells; however, the interplay among metabolic state, osteoclast differentiation and macropinocytosis in bone-related diseases remains poorly understood.</div></div><div><h3>Methods</h3><div>In this study, osteoclast differentiation was induced using murine bone marrow-derived macrophages and RAW 264.7 cells to investigate the role of macropinocytosis in metabolic regulation. Lipopolysaccharide (LPS) was applied to mimic inflammatory conditions in vitro to assess the influence of macropinocytosis on both metabolic profiles and inflammation-associated osteoclastogenesis. Additionally, ligature-induced periodontitis and ovariectomy (OVX)-induced bone loss models in mice were employed to evaluate the in vivo impact of macropinocytosis on bone resorption.</div></div><div><h3>Results</h3><div>Enhanced macropinocytosis promoted osteoclast formation, with LPS further accelerating differentiation and increasing macropinocytic activity. This upregulation helped to meet the energy requirements of osteoclastogenesis via oxidative phosphorylation and glycolysis. Inhibition of macropinocytosis with (N-ethyl-N-isopropyl) amiloride (EIPA) reduced energy production and suppressed osteoclast differentiation. Elevated macropinocytosis was also observed in the periodontitis and OVX models, and its inhibition led to early, dose-dependent restoration of bone mass.</div></div><div><h3>Conclusion</h3><div>Macropinocytosis provides a critical energy source for osteoclast differentiation. Targeting this pathway with EIPA represents a promising therapeutic approach for bone-related diseases.</div></div><div><h3>The translational potential of this article</h3><div>As a bulk endocytic process, macropinocytosis offers a novel therapeutic target for bone-related diseases. The efficacy of EIPA in suppressing osteoclastogenesis and bone resorption suggests its potential as a clinical intervention drug.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 267-279"},"PeriodicalIF":5.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220805","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":"Histone modifications: Unveiling the epigenetic enigma of degenerative skeletal diseases","authors":"Yao Zhang ,&nbsp;Jiale Wang ,&nbsp;Di Hua ,&nbsp;Chunyang Fan ,&nbsp;Wei He ,&nbsp;Yongkang Deng ,&nbsp;Maoting Tang ,&nbsp;Dechun Geng ,&nbsp;Xiexing Wu ,&nbsp;Haiqing Mao","doi":"10.1016/j.jot.2025.08.013","DOIUrl":"10.1016/j.jot.2025.08.013","url":null,"abstract":"<div><div>Degenerative skeletal diseases, including osteoporosis, osteoarthritis, and intervertebral disc degeneration, are prevalent age-related conditions characterized by progressive tissue degeneration and functional decline. Histone modifications are covalent modifications of histone residues, catalyzed by specific enzymes, that modulate chromatin architecture and transcriptional activity. Accumulating evidence highlights the critical involvement of histone modifications in orchestrating disease-associated transcriptional programs. In osteoporosis, histone modifications regulate osteoblast and osteoclast differentiation, thereby disrupting bone homeostasis. In osteoarthritis, they drive the expression of matrix-degrading enzymes in chondrocytes, contributing to cartilage degradation. In intervertebral disc degeneration, they are implicated in nucleus pulposus cell senescence, apoptosis, and extracellular matrix degradation. This review summarizes the distinct mechanistic roles of histone modifications across these conditions and explores the therapeutic potential of targeting histone-modifying enzymes, underscoring epigenetic regulation as a promising strategy for precision intervention in degenerative skeletal diseases.</div><div>The translational potential of this article: This review comprehensively explores the role of histone modifications in degenerative skeletal diseases and evaluates the potential of histone-modifying enzyme inhibitors as therapeutic targets. These insights provide new strategies and directions for the treatment of degenerative skeletal diseases.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 245-266"},"PeriodicalIF":5.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096426","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":"An aptamer specifically targeting mCRP ameliorates experimental arthritis","authors":"Zhuqian Wang ,&nbsp;Duoli Xie ,&nbsp;Peixi Zhu ,&nbsp;Jianmin Guo ,&nbsp;Chunhao Cao ,&nbsp;Yu Du ,&nbsp;Aiping Lu ,&nbsp;Chao Liang","doi":"10.1016/j.jot.2025.08.010","DOIUrl":"10.1016/j.jot.2025.08.010","url":null,"abstract":"<div><h3>Background</h3><div>Recent evidence highlights the important role of the liver–bone axis in the development of arthritis, particularly rheumatoid arthritis (RA) and osteoarthritis (OA). The liver secretes various factors that impact joint health, one of which is C-reactive protein (CRP), elevated in RA and OA patients. Traditionally regarded as an inflammatory marker, the causal role of CRP in arthritis development remains a topic of debate due to the existence of its two isoforms with opposing functions: native pentameric CRP (nCRP) and monomeric CRP (mCRP).</div></div><div><h3>Methods</h3><div>We generated hepatocyte-specific CRP knockout mice to investigate the causal role of CRP in RA and OA mouse models. <em>In vitro</em> experiments were conducted to assess the effects of mCRP and nCRP on phenotypic changes in effector cells common to RA and OA, including fibroblast-like synoviocytes (FLSs), monocytes/macrophages, and chondrocytes. Using systematic evolution of ligands by exponential enrichment (SELEX), we screened nucleic acid aptamers targeting mCRP rather than nCRP. We determined the neutralizing effects of the selected aptamers on mCRP <em>in vitro</em> and explored their therapeutic potential and safety in RA and OA mouse models.</div></div><div><h3>Results</h3><div>Hepatocyte-specific knockout of CRP significantly reduced disease severity in RA and OA mouse models. mCRP promoted <em>in vitro</em> pathological changes in FLSs, monocytes/macrophages, and chondrocytes, while nCRP exhibited minimal or slightly protective effects. We identified an aptamer, ApmCRP3, which effectively inhibited mCRP-induced pathological changes of RA and OA effector cells <em>in vitro</em>. In mouse models of RA and OA, ApmCRP3 displayed strong therapeutic effects and a favorable safety profile.</div></div><div><h3>Conclusion</h3><div>This study identifies hepatocyte-derived mCRP as a contributor to RA and OA pathogenesis and highlights ApmCRP3 aptamer as a promising therapeutic candidate.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the therapeutic potential of ApmCRP3 in attenuating mCRP-driven pathology and controlling arthritis progression.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 228-244"},"PeriodicalIF":5.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096427","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":"Advanced bioactive materials and strategies for tendon repair and function restoration","authors":"Sidan Wang ,&nbsp;Zixuan Ou ,&nbsp;Feng Xiao ,&nbsp;Xiaobo Feng ,&nbsp;Lei Tan ,&nbsp;Shuangshuang Cheng ,&nbsp;Di Wu ,&nbsp;Cao Yang ,&nbsp;Haoqun Yao","doi":"10.1016/j.jot.2025.08.012","DOIUrl":"10.1016/j.jot.2025.08.012","url":null,"abstract":"<div><div>Tendon injury is one of the most common clinical challenges in musculoskeletal disorders. Effective tendon repair is crucial for restoring patients' motor function and improving their quality of life. Recent advances in bioactive material-mediated tendon regeneration have shown great therapeutic potential and clinical relevance. However, systematic reviews that comprehensively integrate these developments are still scarce. Firstly, this article presents the selection of bioactive components, mainly including cell-based therapeutic strategies and nanodrug delivery strategies. Secondly, bioactive materials delivery system using tissue-engineered scaffolds is discussed in detail. In this section, we discuss the efficacy of scaffolds in tendon repair through different scaffold preparation methods and synthetic raw materials. Furthermore, the application of hydrogel systems such as enhanced hydrogels, bioadhesive hydrogels and multifunctional hydrogels in tendon repair strategies is systematically and comprehensively presented. Finally, based on a detailed review of the field, current challenges in the field were proposed and potential research directions in the field were identified, including potential research directions in smart bioactive materials and personalized treatment strategies.</div></div><div><h3>The translational potential of this article</h3><div>This review synthesizes tendon regeneration strategies—from molecular mechanisms to tissue-level integration—including bioactive component selection and delivery systems using tissue-engineered scaffolds. It identifies translational barriers and proposes new strategies in tendon-specific safety validation, scalable manufacturing uniformity and cost-effectiveness versus conventional therapies. These insights will refine clinical strategies for tendon injuries and advance targeted bioactive biomaterials for localized regeneration.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 204-227"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060059","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":"Development and multi-center validation of a software program, Ofeye 3.0, for automated all-inclusive vertebral fracture detection with chest/abdominal CT images","authors":"Ben-Heng Xiao ,&nbsp;Zhen-Hua Gao ,&nbsp;Cai-Ying Li ,&nbsp;Xiao-Ming Leng ,&nbsp;Er-Zhu Du ,&nbsp;Jian-Bing Ma ,&nbsp;Fu-Shan Liu ,&nbsp;Jing-Shan Gong ,&nbsp;Zhi-Guo Ju ,&nbsp;Ming-Yuan Yuan ,&nbsp;Hui-Ming Zhu ,&nbsp;Michael S.Y. Zhu ,&nbsp;Timothy YC. Kwok ,&nbsp;Yì Xiáng J. Wáng","doi":"10.1016/j.jot.2025.08.011","DOIUrl":"10.1016/j.jot.2025.08.011","url":null,"abstract":"<div><h3>Background</h3><div>Missing report for fragility vertebral fracture (VF) on chest/abdominal CT is common when the indication is not spine disorders. This represents a missed opportunity to alert patients to take preventive measures to improve bone health and prevent further severe fractures. In this study, we aim to develop a software program for automated detection of VF with existing chest/abdominal CT scans and validate its detection performance.</div></div><div><h3>Methods</h3><div>An automated sagittal Central Slab reconstruction (CSR) method for CT axial images was developed. For reference VF reading<em>,</em> VFs inclusive of those of with &lt;20 % vertebral height loss and those of endplate fracture with minimal vertebral height loss were identified. VFs were also differentiated from osteoarthritic wedging and endplatitis short vertebrae. Prior knowledge of VF detection models for lateral radiograph were transferred to a new ‘Ofeye 3.0’ model optimized for VF detection on CT image. Training CT images were obtained from nine centers, totaling 3313 cases without VF and 835 cases with VF. For external validation, CT images were from five centers totaling 732 cases without VF and 224 cases with VF.</div></div><div><h3>Results</h3><div>The automated CSR method showed advantages in demonstrating structural changes of the endplate and adjacent structures. For detecting VF in chest/abdominal CT scans, counting case-by-case and compared with the reference reading, the average performance of Ofeye 3.0 was accuracy 0.967, sensitivity 0.906, and specificity 0.986. Most of false negative or false positive cases were minimal or mild VF, or with image artifacts, or with VF close to the peripheral of CSR images.</div></div><div><h3>Conclusions</h3><div>Despite the challenging requirements for the software to detect all-inclusive VF, our results compare favorably with other published automated VF detection models.</div></div><div><h3>The translational potential of this article</h3><div>We developed a software program for automated all-inclusive VF detection on chest and/or abdominal CT image data and conducted a multi-center external validation study. This software is proved to have high VF detection precision. By alerting patients of the VFs likely related to osteoporosis and in turn the patients taking measures to prevent further fracture, the integration of this software into radiological practice will improve patient outcomes and reduce healthcare costs.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 192-203"},"PeriodicalIF":5.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045683","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}