Journal of Orthopaedic Translation最新文献

{"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":"2025-11-01","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":"Corrigendum to ‘Netrin-1 mediates nerve innervation and angiogenesis leading to discogenic pain’ [J Orthop Translat, Volume 39 (2023), pages 21-33/ID: JOTr-D-22-00248]","authors":"Bingjie Zheng ,&nbsp;Shengwen Li ,&nbsp;Yufeng Xiang ,&nbsp;Wentian Zong ,&nbsp;Qingliang Ma ,&nbsp;Shiyu Wang ,&nbsp;Haihao Wu ,&nbsp;Haixin Song ,&nbsp;Hong Ren ,&nbsp;Jian Chen ,&nbsp;Junhui Liu ,&nbsp;Fengdong Zhao","doi":"10.1016/j.jot.2025.06.017","DOIUrl":"10.1016/j.jot.2025.06.017","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 376-378"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786637","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":"Neuropeptide Y1 receptor antagonist alleviated osteoarthritis by restoring chondrocyte autophagy through PI3K/AKT/mTOR signaling pathway","authors":"Song Liu ,&nbsp;Jianqun Wu ,&nbsp;Yucong Lin ,&nbsp;Haifeng Liang ,&nbsp;Yu Cai ,&nbsp;Le Wang ,&nbsp;Zhao Wang ,&nbsp;Hongxun Sang","doi":"10.1016/j.jot.2025.08.003","DOIUrl":"10.1016/j.jot.2025.08.003","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Osteoarthritis (OA) is a debilitating joint disorder affecting millions worldwide, characterized by progressive cartilage degradation and chronic pain. Emerging evidence suggests that neuropeptide Y (NPY) and its Y1 receptors are involved in OA pathogenesis, although the underlying molecular mechanisms remain poorly understood. This study investigates the role of NPY/Y1R signaling in OA progression through PI3K/AKT/mTOR-mediated regulation of chondrocyte autophagy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Human cartilage samples were collected from ten OA patients (3 male,7 female, 63–75 years old) undergoing total knee arthroplasty and graded using the Kellgren–Lawrence system. Primary chondrocytes were isolated from neonatal C57BL/6 mice and treated with NPY (0.01–5 μM) or interleukin-1β (IL-1β, 10 ng/mL) to mimic OA-like degeneration. RNA sequencing (RNA-seq) and KEGG pathway analysis were performed to identify NPY-regulated signaling pathways. &lt;em&gt;In vivo&lt;/em&gt;, OA was induced in 8-week-old male C57BL/6 mice via destabilization of the medial meniscus (DMM) or intra-articular injections of NPY (5 μM, every 4 weeks). Mice were treated with the Y1R antagonist (0.1 μM, weekly) or vehicle control. Pain behavior was assessed using von Frey filaments and CatWalk gait analysis. Cartilage degeneration was evaluated via histology (Safranin O/Fast Green, OARSI scoring), immunofluorescence (COLII, MMP13, LC3-II, p62), and micro-CT (subchondral bone remodeling, osteophyte formation). The activation status of the PI3K/AKT/mTOR pathway and autophagy-related markers was determined via Western blotting and immunofluorescence assays under both &lt;em&gt;in vitro&lt;/em&gt; and &lt;em&gt;in vivo&lt;/em&gt; conditions.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;NPY and Y1R expression were significantly elevated in human OA cartilage compared to normal tissue. &lt;em&gt;In vitro&lt;/em&gt;, NPY (5 μM) suppressed chondrocyte proliferation, reduced COLII expression, and increased MMP13 production. RNA-seq revealed NPY-mediated activation of the PI3K/AKT/mTOR pathway and inhibition of autophagy-related genes. NPY treatment enhanced the phosphorylation levels of PI3K, AKT, and mTOR, while concurrently decreasing LC3II expression and increasing p62 accumulation. The Y1R antagonist reversed these effects, restoring autophagy and attenuating cartilage degradation. &lt;em&gt;In vivo&lt;/em&gt;, NPY injections induced OA-like changes, including cartilage thinning, osteophyte formation, and mechanical allodynia. Y1R antagonist treatment mitigated these effects, improving gait parameters and reducing subchondral bone sclerosis. Immunofluorescence confirmed that Y1R inhibition decreased PI3K/AKT/mTOR signaling and enhanced autophagy in chondrocytes.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This study demonstrates that NPY/Y1R signaling exacerbates OA progression through PI3K/AKT/mTOR-mediated suppression of chondrocyte autophagy. Pharmacological inhibition of Y1R emerges as a novel therapeutic strategy, e","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 146-158"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045686","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":"2025-11-01","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":"Can alternatives to animal testing yield useful information regarding biological mechanisms and drug discovery?","authors":"Qi Gao,&nbsp;Simon Kwoon-Ho Chow,&nbsp;Issei Shinohara,&nbsp;Masatoshi Murayama,&nbsp;Yosuke Susuki,&nbsp;Mayu Morita,&nbsp;Chao Ma,&nbsp;Stuart B. Goodman","doi":"10.1016/j.jot.2025.08.005","DOIUrl":"10.1016/j.jot.2025.08.005","url":null,"abstract":"<div><div>Establish alternative strategies to standard animal experiments decrease animal utilization and simultaneously enhance the reliability of biological and disease models. This review highlights advancements in three areas: in vitro culture platforms, disease modeling, and in silico simulations. We first discuss the innovative in vitro approaches, including 2D coculture systems, 3D spheroids, organoids, and organ-on-chip models, which facilitate the creation of physiologically relevant environments. Then, we focus on cell selection and characterization in disease modeling, with a particular focus on bone fracture healing and inflammation. We further review the potential of in silico simulations, including molecular docking, machine learning (ML) approaches, and pharmacokinetics-pharmacodynamics (PK/PD) modeling, to predict drug efficacy, interactions, and biological outcomes. These alternative strategies provide the potential for obtaining accurate and consistent results, thereby enhancing biomedical research and decreasing dependence on animal models. The Translational Potential of this Article: This review examines in vitro organoids, microphysiological systems, and computational models as alternatives to animal testing. These methods enhance our understanding of biological mechanisms. They also reduce the requirement for animal models. Ultimately, they help accelerate drug discovery that can directly benefit patients.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 132-145"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045687","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":"2025-11-01","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":"Classification and pathoanatomy of posterior malleolus fracture based on posterior malleolus-associated ligaments and ankle stability","authors":"Yongqi Li ,&nbsp;Yi Liao ,&nbsp;Rui Luo ,&nbsp;Tian Zhao ,&nbsp;Shun Wang ,&nbsp;Yunfeng Yang","doi":"10.1016/j.jot.2025.09.003","DOIUrl":"10.1016/j.jot.2025.09.003","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;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 %).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;The clinical signifi","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 339-345"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","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":"Natural products in the treatment of osteoarthritis: Current status and prospects","authors":"Chenyue Xu ,&nbsp;Xiaoyu Cui ,&nbsp;Yuhang Shi ,&nbsp;Tianhang Zhang ,&nbsp;Zhengyi Ni ,&nbsp;Kehan Li ,&nbsp;Xiaobo Chen ,&nbsp;Fei Wang","doi":"10.1016/j.jot.2025.07.007","DOIUrl":"10.1016/j.jot.2025.07.007","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone remodeling. Existing treatments primarily offer symptomatic relief without effectively delaying OA progression. Recently, natural products have attracted great interest due to their anti-inflammatory, antioxidant, and chondroprotective effects. This review systematically summarized the efficacy and mechanisms of 13 natural products (Curcumin, Resveratrol, Icariin, Sinomenine, Andrographolide, Apigenin, Salvianolic acid, Matrine, Hesperidin, Plumbagin, Pomegranate extract, Thymoquinone, and Madecassoside) in OA treatment, drawing on evidence from in vitro and in vivo animal models, as well as clinical trials. By elucidating the current research status and future prospects, our review seeks to provide robust evidence for innovative and effective treatment strategies based on natural products to improve patient outcomes in OA management.</div></div><div><h3>The translational potential of this article</h3><div>This review enhances our comprehension of the pathological mechanisms underlying OA, delineates the existing therapeutic approaches for OA, their inherent limitations, and elucidates the current status and future prospects of natural products in OA management. With further clinical validation, these natural products may serve as adjunctive or alternative therapies to improve long-term outcomes in OA patients.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 94-120"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009855","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":"2025-11-01","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":"Targeting MAT2A synergistically induces DNA damage in osteosarcoma cells through EZH2-mediated H3K27me3 modification","authors":"Binghui Yang ,&nbsp;Haoyu Wang ,&nbsp;Yining Tao ,&nbsp;Xiyu Yang ,&nbsp;Haoran Mu ,&nbsp;Liu Yang ,&nbsp;Yafei Jiang ,&nbsp;Zhuoying Wang ,&nbsp;Rui Zhang ,&nbsp;Zhengdong Cai ,&nbsp;Chunxi Yang ,&nbsp;Dongqing Zuo ,&nbsp;Yingqi Hua ,&nbsp;Wei Sun","doi":"10.1016/j.jot.2025.09.007","DOIUrl":"10.1016/j.jot.2025.09.007","url":null,"abstract":"<div><h3>Background</h3><div>Osteosarcoma (OS) is a highly aggressive primary bone tumor with poor outcomes, particularly in metastatic or recurrent cases. Methionine metabolism and histone methylation, such as H3K27me3, play crucial roles in OS progression.</div></div><div><h3>Methods</h3><div>We analyzed single-cell RNA sequencing (scRNA-seq) data to identify histone methylation and related pathways associated with malignant proliferation OS cells. A high-throughput compound screen was performed to evaluate potential metabolic and epigenetic targets. In vitro and in vivo experiments were conducted to assess the therapeutic potential of MAT2A inhibition, methionine restriction, and EZH2 inhibition.</div></div><div><h3>Results</h3><div>MAT2A inhibition or methionine restriction reduced H3K27me3 levels, induced DNA damage, and suppressed OS cell growth. Combining MAT2A and EZH2 inhibitors demonstrated synergistic effects in reducing H3K27me3 levels, enhancing DNA damage, and inhibiting OS growth both in vitro and in vivo.</div></div><div><h3>Conclusion</h3><div>The combination of MAT2A and EZH2 inhibition significantly reduces intracellular H3K27me3 levels by depleting S-adenosylmethionine (SAM) and inhibiting synthetic enzyme activity, thereby inducing DNA damage in osteosarcoma (OS). Methionine-restricted diet combined with EZH2 inhibition effectively suppresses osteosarcoma growth in vivo.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the potential of integrating metabolic and epigenetic interventions in OS therapy. Our findings might present a promising therapeutic strategy for chemotherapy-resistance OS.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 346-359"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145320061","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}