Pub Date : 2025-11-01DOI: 10.1016/j.jot.2025.04.016
Zihao Yao , Zhikun Yuan , Yanhui Li , Xuming Li , Changgui Peng , Junyu Jin , Haiyan Zhang , Xiaochun Bai , Jianying Pan , Daozhang Cai
<div><h3>Background</h3><div>Osteoarthritis (OA) is a globally prevalent degenerative joint disease, characterized by cartilage degradation and synovial inflammation. Increasing evidence suggests that macrophages in the synovium play a pivotal role in OA pathogenesis. Energy metabolism reprogramming has emerged as a key regulator of macrophage activation in inflammatory diseases. Long-chain fatty acid-CoA ligase 1 (ACSL1), an enzyme critical for lipid metabolism, has been implicated in various diseases. However, the specific mechanism by which ACSL1 regulates macrophage polarization and contributes to OA progression remains unclear.</div></div><div><h3>Methods</h3><div>In this study, we examined ACSL1 expression in the hyperplastic synovium of patients with knee OA and in a mouse model of OA induced by destabilization of the medial meniscus (DMM). We isolated bone marrow-derived macrophages (BMDMs) from C57 mice and transfected them with ACSL1 knockdown plasmids to assess the impact of ACSL1 on macrophage polarization and inflammatory cytokine release. We also investigated the effect of ACSL1 knockdown on cartilage degradation using BMDM supernatant in cartilage explant cultures. Intra-articular injection of AAV-shACSL1 was performed to evaluate its effect on OA progression in a trauma-induced mouse model. The expression of ACSL1, inflammatory cytokines (IL-1, IL-6, TNF-α), and lipopolysaccharide (LPS)-induced macrophage polarization markers (M1 and M2 markers) was assessed using qRT-PCR, Western blotting, and ELISA. Lipid peroxidation and the activation of the IκB/NF-κB signaling pathway were examined to elucidate the mechanism by which ACSL1 regulates inflammation.</div></div><div><h3>Results</h3><div>We observed increased ACSL1 expression in both the hyperplastic synovium of OA patients and the synovium of DMM-induced OA mice. Knockdown of ACSL1 in macrophages inhibited M1 polarization and reduced the release of key inflammatory cytokines, including IL-1, IL-6, and TNF-α. Furthermore, supernatants from ACSL1-knockdown BMDMs mitigated cartilage degradation in explant cultures. Intra-articular injection of AAV-shACSL1 reduced OA progression in a mouse model of trauma-induced OA. Mechanistically, ACSL1 knockdown alleviated LPS-induced inflammation by inhibiting lipid peroxidation and reducing the activation of the IκB/NF-κB pathway, a major regulator of inflammatory responses in macrophages.</div></div><div><h3>Conclusions</h3><div>ACSL1 plays a crucial role in regulating the inflammatory state of synovial macrophages in OA. By modulating macrophage polarization and lipid peroxidation, ACSL1 contributes to the progression of OA. Targeting ACSL1 could provide a novel therapeutic strategy for the prevention and treatment of OA.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the pivotal role of ACSL1 in regulating macrophage-mediated inflammation in OA. Targeting ACSL1 expression or its associated path
{"title":"Upregulation of ACSL1 in synovial macrophages promotes lipid peroxidation via the IκB/NF-κB pathway to accelerate osteoarthritis","authors":"Zihao Yao , Zhikun Yuan , Yanhui Li , Xuming Li , Changgui Peng , Junyu Jin , Haiyan Zhang , Xiaochun Bai , Jianying Pan , Daozhang Cai","doi":"10.1016/j.jot.2025.04.016","DOIUrl":"10.1016/j.jot.2025.04.016","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a globally prevalent degenerative joint disease, characterized by cartilage degradation and synovial inflammation. Increasing evidence suggests that macrophages in the synovium play a pivotal role in OA pathogenesis. Energy metabolism reprogramming has emerged as a key regulator of macrophage activation in inflammatory diseases. Long-chain fatty acid-CoA ligase 1 (ACSL1), an enzyme critical for lipid metabolism, has been implicated in various diseases. However, the specific mechanism by which ACSL1 regulates macrophage polarization and contributes to OA progression remains unclear.</div></div><div><h3>Methods</h3><div>In this study, we examined ACSL1 expression in the hyperplastic synovium of patients with knee OA and in a mouse model of OA induced by destabilization of the medial meniscus (DMM). We isolated bone marrow-derived macrophages (BMDMs) from C57 mice and transfected them with ACSL1 knockdown plasmids to assess the impact of ACSL1 on macrophage polarization and inflammatory cytokine release. We also investigated the effect of ACSL1 knockdown on cartilage degradation using BMDM supernatant in cartilage explant cultures. Intra-articular injection of AAV-shACSL1 was performed to evaluate its effect on OA progression in a trauma-induced mouse model. The expression of ACSL1, inflammatory cytokines (IL-1, IL-6, TNF-α), and lipopolysaccharide (LPS)-induced macrophage polarization markers (M1 and M2 markers) was assessed using qRT-PCR, Western blotting, and ELISA. Lipid peroxidation and the activation of the IκB/NF-κB signaling pathway were examined to elucidate the mechanism by which ACSL1 regulates inflammation.</div></div><div><h3>Results</h3><div>We observed increased ACSL1 expression in both the hyperplastic synovium of OA patients and the synovium of DMM-induced OA mice. Knockdown of ACSL1 in macrophages inhibited M1 polarization and reduced the release of key inflammatory cytokines, including IL-1, IL-6, and TNF-α. Furthermore, supernatants from ACSL1-knockdown BMDMs mitigated cartilage degradation in explant cultures. Intra-articular injection of AAV-shACSL1 reduced OA progression in a mouse model of trauma-induced OA. Mechanistically, ACSL1 knockdown alleviated LPS-induced inflammation by inhibiting lipid peroxidation and reducing the activation of the IκB/NF-κB pathway, a major regulator of inflammatory responses in macrophages.</div></div><div><h3>Conclusions</h3><div>ACSL1 plays a crucial role in regulating the inflammatory state of synovial macrophages in OA. By modulating macrophage polarization and lipid peroxidation, ACSL1 contributes to the progression of OA. Targeting ACSL1 could provide a novel therapeutic strategy for the prevention and treatment of OA.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the pivotal role of ACSL1 in regulating macrophage-mediated inflammation in OA. Targeting ACSL1 expression or its associated path","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 360-375"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786636","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}
Pub Date : 2025-11-01DOI: 10.1016/j.jot.2025.06.018
Bin Liu , Guanhui Song , Yaosheng Wang , Changheng Song , Yiping Cao , Jinlin Tong , Yuyao Wang , Xinrong Fan , Nannan Shi , Hongyan Zhao , Danping Fan
{"title":"Corrigendum to ‘N6-methyladenosine and intervertebral disc degeneration: Advances in detection and pathological insights’ [J Orthop Translat 53 (2025) 38–51/JOT 941]","authors":"Bin Liu , Guanhui Song , Yaosheng Wang , Changheng Song , Yiping Cao , Jinlin Tong , Yuyao Wang , Xinrong Fan , Nannan Shi , Hongyan Zhao , Danping Fan","doi":"10.1016/j.jot.2025.06.018","DOIUrl":"10.1016/j.jot.2025.06.018","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Page 379"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786638","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}
Pub Date : 2025-11-01DOI: 10.1016/j.jot.2025.06.017
Bingjie Zheng , Shengwen Li , Yufeng Xiang , Wentian Zong , Qingliang Ma , Shiyu Wang , Haihao Wu , Haixin Song , Hong Ren , Jian Chen , Junhui Liu , Fengdong Zhao
{"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 , Shengwen Li , Yufeng Xiang , Wentian Zong , Qingliang Ma , Shiyu Wang , Haihao Wu , Haixin Song , Hong Ren , Jian Chen , Junhui Liu , 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}
Pub Date : 2025-10-16DOI: 10.1016/j.jot.2025.09.007
Binghui Yang , Haoyu Wang , Yining Tao , Xiyu Yang , Haoran Mu , Liu Yang , Yafei Jiang , Zhuoying Wang , Rui Zhang , Zhengdong Cai , Chunxi Yang , Dongqing Zuo , Yingqi Hua , Wei Sun
Background
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.
Methods
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.
Results
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.
Conclusion
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.
The translational potential of this article
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.
{"title":"Targeting MAT2A synergistically induces DNA damage in osteosarcoma cells through EZH2-mediated H3K27me3 modification","authors":"Binghui Yang , Haoyu Wang , Yining Tao , Xiyu Yang , Haoran Mu , Liu Yang , Yafei Jiang , Zhuoying Wang , Rui Zhang , Zhengdong Cai , Chunxi Yang , Dongqing Zuo , Yingqi Hua , 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":"2025-10-16","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}
Pub Date : 2025-10-10DOI: 10.1016/j.jot.2025.09.003
Yongqi Li , Yi Liao , Rui Luo , Tian Zhao , Shun Wang , Yunfeng Yang
<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
{"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}
Pub Date : 2025-10-01DOI: 10.1016/j.jot.2025.08.014
Ziyu Chen , Zhi Yao , Mengfan Wu , Yuluan Wu , Jianlin Zhang , Zhuangyao Liao , Junyu Qian , Jiewen Wei , Lili Song , Longbiao Yu , Jingjing Wen , Zhegang Zhou , Yihao Wei , Yuefeng Yao , Zetao Ma , Pei Liu , Shailesh Agarwal , Ye Li , Lixiang Xue , Deli Wang
Background
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.
Methods
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.
Results
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.
Conclusion
EZH2 inhibitors exerted potent anti-fibrotic effects in secondary lymphedema though activating PPARγ signaling, offering novel insights and strategies for fibrotic disorders.
The translational potential of this article
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.
{"title":"Epigenetic reprogramming via EZH2 inhibition rescues fibroadipose pathogenesis in secondary lymphedema through activating PPARγ signaling","authors":"Ziyu Chen , Zhi Yao , Mengfan Wu , Yuluan Wu , Jianlin Zhang , Zhuangyao Liao , Junyu Qian , Jiewen Wei , Lili Song , Longbiao Yu , Jingjing Wen , Zhegang Zhou , Yihao Wei , Yuefeng Yao , Zetao Ma , Pei Liu , Shailesh Agarwal , Ye Li , Lixiang Xue , 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}
Pub Date : 2025-10-01DOI: 10.1016/j.jot.2025.09.004
Zhichao Li , Kuanhui Gao , Mengjie Wang , Songlin Liang , Dandan Li , Peng Zhang , Wenxiang Cheng , Zhanwang Xu , Nianhu Li
Background
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.
Methods
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 in vivo overexpression or pharmacological inhibition.
Results
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.
Conclusion
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.
The translational potential of this article
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.
{"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 , Kuanhui Gao , Mengjie Wang , Songlin Liang , Dandan Li , Peng Zhang , Wenxiang Cheng , Zhanwang Xu , 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}
Pub Date : 2025-09-30DOI: 10.1016/j.jot.2025.09.002
Ning Chen , Mengdan Zhang , Baohong Shi , Xiumei Luo , Rui Huang , Zhengqiong Luo , Junliang He , Shengye Xue , Na Li , Zemin Ling , Hao Guo , Ren Xu , Yuejun Liu
<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>1. The effect of Tirzepatide on osteoblasts and osteoclasts was observed by inducing differentiation of bone marrow mesenchymal cells (BMSCs) <em>in vitro</em>. 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 <em>in vitro</em> intervention of differential metabolites in BMSCs induction differentiation experiments.</div></div><div><h3>Results</h3><div>We found that TZP intervention resulted in a significant decrease in bone mass accrual <em>in vivo</em>. TZP was not indispensable to the differentiation of osteoblasts and osteoclasts <em>in vitro</em>. 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. <em>Lachnospiraceae</em>, a key pro-osteogenic component of gut microbiota was significantly reduced. As a main metabolite of <em>Lachnospiraceae</em>, evodiamine played a role in suppressing osteoclastogenesis <em>in vitro</em>. Based on this, the transplantation of the <em>Lachnospiraceae</em> effectively ameliorated bone loss that was seen in db/db mice due to TZP treatment.</div></div><div><h3>Conclusion</h3><div>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.</div></div><div><h3>The translational potential of this article</h3><div>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.</div></di
{"title":"Tirzepatide, a dual GLP-1 and GIP receptor agonist, promotes bone loss in obese mice via gut microbial-related metabolites","authors":"Ning Chen , Mengdan Zhang , Baohong Shi , Xiumei Luo , Rui Huang , Zhengqiong Luo , Junliang He , Shengye Xue , Na Li , Zemin Ling , Hao Guo , Ren Xu , Yuejun Liu","doi":"10.1016/j.jot.2025.09.002","DOIUrl":"10.1016/j.jot.2025.09.002","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>1. The effect of Tirzepatide on osteoblasts and osteoclasts was observed by inducing differentiation of bone marrow mesenchymal cells (BMSCs) <em>in vitro</em>. 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 <em>in vitro</em> intervention of differential metabolites in BMSCs induction differentiation experiments.</div></div><div><h3>Results</h3><div>We found that TZP intervention resulted in a significant decrease in bone mass accrual <em>in vivo</em>. TZP was not indispensable to the differentiation of osteoblasts and osteoclasts <em>in vitro</em>. 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. <em>Lachnospiraceae</em>, a key pro-osteogenic component of gut microbiota was significantly reduced. As a main metabolite of <em>Lachnospiraceae</em>, evodiamine played a role in suppressing osteoclastogenesis <em>in vitro</em>. Based on this, the transplantation of the <em>Lachnospiraceae</em> effectively ameliorated bone loss that was seen in db/db mice due to TZP treatment.</div></div><div><h3>Conclusion</h3><div>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.</div></div><div><h3>The translational potential of this article</h3><div>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.</div></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}
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.
Methods
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 vitro, 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.
Results
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.
Conclusion
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.
The translational potential of this article
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.
{"title":"Cuproptosis in osteoarthritis: Exploring chondrocyte cuproptosis and therapeutic avenues","authors":"Haotian Hua , Feng Cheng , Zhuo Meng , Anqi Zhang , Mengying Li , Minjie Zhang , Pengqiang Lou , Yiwen Zhu , Peijian Tong , 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}
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