Pub Date : 2025-09-01Epub Date: 2025-07-16DOI: 10.1016/j.jot.2025.07.004
Xin Jin , Lin Huang , Xueyan Wang , Yun Tan , Miao Huang , Haijing Fu , Chengping Wen , Mingqian Zhou
As an emerging three-dimensional (3D) cell culture model, synovial organoids can highly mimic the structure and function of synovial tissue in vivo, providing a new and powerful tool for the research of synovial-related diseases. This article elaborated in detail on the construction of synovial organoids from the cell sources, culture systems, and construction techniques. Meanwhile, it comprehensively reviewed the application progress of synovial organoids in arthritic diseases including rheumatoid arthritis and osteoarthritis such as disease pathogenesis, drug development, and personalized therapy. Additionally, it explores current challenges and future directions for synovial organoids, providing a reference for further research and applications in related-diseases.
The Translational Potential of this Article
Synovial organoids enable direct modeling of the human synovial joint, offering a physiologically relevant platform for high-throughput drug screening. Patient-derived organoids not only facilitate the development of personalized medicine but also reduce reliance on animal studies for preclinical validation. This approach addresses ethical challenges and species-specific limitations while enhancing the translational relevance to human disease mechanisms.
{"title":"Synovial organoids: From fundamental construction to groundbreaking applications in arthritic disorders","authors":"Xin Jin , Lin Huang , Xueyan Wang , Yun Tan , Miao Huang , Haijing Fu , Chengping Wen , Mingqian Zhou","doi":"10.1016/j.jot.2025.07.004","DOIUrl":"10.1016/j.jot.2025.07.004","url":null,"abstract":"<div><div>As an emerging three-dimensional (3D) cell culture model, synovial organoids can highly mimic the structure and function of synovial tissue in vivo, providing a new and powerful tool for the research of synovial-related diseases. This article elaborated in detail on the construction of synovial organoids from the cell sources, culture systems, and construction techniques. Meanwhile, it comprehensively reviewed the application progress of synovial organoids in arthritic diseases including rheumatoid arthritis and osteoarthritis such as disease pathogenesis, drug development, and personalized therapy. Additionally, it explores current challenges and future directions for synovial organoids, providing a reference for further research and applications in related-diseases.</div><div>The Translational Potential of this Article</div><div>Synovial organoids enable direct modeling of the human synovial joint, offering a physiologically relevant platform for high-throughput drug screening. Patient-derived organoids not only facilitate the development of personalized medicine but also reduce reliance on animal studies for preclinical validation. This approach addresses ethical challenges and species-specific limitations while enhancing the translational relevance to human disease mechanisms.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 26-36"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633916","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 : 2025-09-01Epub Date: 2025-07-16DOI: 10.1016/j.jot.2025.06.020
Jingtao Huang , Shicheng Jia , Rongji Liang , Aikang Li , Lin Li , Haojian Wang , Jiayou Chen , Haoxian Tang , Xuan Zhang , Jianjing Lin , Xintao Zhang
Articular cartilage defects caused by trauma or degeneration severely impair patient function. Cartilage repair organoids represent a transformative approach in regenerative medicine to address these challenges. This review focuses on the development and therapeutic potential of such organoids, detailing their role in overcoming limitations of conventional treatments. Central to this progress, bioprinting technology enables precise organoid fabrication by advancing organoid-compatible bioinks and printing techniques. We further examine applications in disease modeling and drug screening, alongside pathways for clinical translation. As organoid engineering matures, it promises to deliver effective, patient-specific solutions for cartilage restoration.
The Translational Potential Statement: The Translational Potential of this Article: 3D-bioprinted cartilage organoids exhibit outstanding efficacy in animal models and hold promise for future clinical trials. The bioinks and printing technologies are distilled to promote basic research toward translation of cartilage repair.
{"title":"Construction of organoids using bioprinting technology: a frontier exploration of cartilage repair","authors":"Jingtao Huang , Shicheng Jia , Rongji Liang , Aikang Li , Lin Li , Haojian Wang , Jiayou Chen , Haoxian Tang , Xuan Zhang , Jianjing Lin , Xintao Zhang","doi":"10.1016/j.jot.2025.06.020","DOIUrl":"10.1016/j.jot.2025.06.020","url":null,"abstract":"<div><div>Articular cartilage defects caused by trauma or degeneration severely impair patient function. Cartilage repair organoids represent a transformative approach in regenerative medicine to address these challenges. This review focuses on the development and therapeutic potential of such organoids, detailing their role in overcoming limitations of conventional treatments. Central to this progress, bioprinting technology enables precise organoid fabrication by advancing organoid-compatible bioinks and printing techniques. We further examine applications in disease modeling and drug screening, alongside pathways for clinical translation. As organoid engineering matures, it promises to deliver effective, patient-specific solutions for cartilage restoration.</div><div>The Translational Potential Statement: The Translational Potential of this Article: 3D-bioprinted cartilage organoids exhibit outstanding efficacy in animal models and hold promise for future clinical trials. The bioinks and printing technologies are distilled to promote basic research toward translation of cartilage repair.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 37-50"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144634441","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 : 2025-09-01Epub Date: 2025-07-23DOI: 10.1016/j.jot.2025.07.005
Baofeng Guo , Sihe Qin , Junming Zhang , Yilan Wang , Lei Shi
<div><h3>Background</h3><div>Limb deformities are almost associated with varying degrees of disability, which severely affects the quality of life and social participation. However, the epidemiological profiles of limb deformities remain underreported. As the world's largest developing country with regional economic disparities, China faces unique challenges in the diagnosis and management of limb deformities. The Qin Sihe Orthopaedic Surgery Database is currently the most comprehensive database of limb deformity in China, which has the largest case volume, the widest disease spectrum, and the broadest geographical coverage, provides an invaluable resource for studying limb deformity patterns in China and other developing countries.</div></div><div><h3>Objective</h3><div>To analyze 37763 limb deformity cases from the Qin Sihe Orthopaedic Surgery Database, and to summarize the etiology distribution, disease spectrum, gender, age, geographical distribution, gait abnormalities and treatment strategies of limb deformities in China.</div></div><div><h3>Methods</h3><div>Descriptive epidemiological methods were used to analyze the data of Qin Sihe Orthopaedic Surgery Database from May 25th, 1978 to December 31st, 2023 containing 37763 cases of Limb deformities. The data on patients' gender, age, etiology distribution, disease spectrum, geographical distribution, gait abnormalities and surgical methods etc will be statistically analyzed.</div></div><div><h3>Results</h3><div>Among 37763 patients, 21815 (57.77 %) were male and 15948 (42.23 %) were female, aged 1–84 years old, covering 33 provinces, municipalities and autonomous regions in China and some international regions. Etiologies included 239 neurogenic, traumatic, congenital and metabolic diseases, among which neurogenic diseases took the dominant portion: 24430 (64. 7 %) cases of post-polio sequelae, 5088 (13. 4 %) cases of cerebral palsy. Lower limb deformities(35,869 cases,95 %) was significantly more than upper limb deformities (646 cases, 1.7 %). The surgical interventions included soft tissue release and tendon lengthening (e. g. Achilles tendon lengthening, 8282 cases, 21.93 %), osteotomy (e.g. supracondylar femoral osteotomy, 7740 cases, 20.50 %), and arthrodesis (e. g. talocalcaneal arthrodesis, 6873 cases, 18.20 %). The fixation methods included Ilizarov external fixation (5611 cases), combined external fixation (5612 cases), combined internal fixation (1805 cases) and plaster or brace immobilization (24735 cases).</div></div><div><h3>Conclusion</h3><div>The causes of limb deformities in China are diverse, and the diseases involves multiple disciplines. Cases are predominantly male and young., Polio sequelae deformity remains the main malformation diseases, but the proportion of cerebral palsy, limb deformities after trauma, lower limb deformities after spina bifida and genetic metabolic diseases are increasing. This study provides important real-world data for the classification of etiol
{"title":"Epidemiological profiles and intervention strategies of limb deformities in China: A nationwide study based on the largest orthopedic database in China","authors":"Baofeng Guo , Sihe Qin , Junming Zhang , Yilan Wang , Lei Shi","doi":"10.1016/j.jot.2025.07.005","DOIUrl":"10.1016/j.jot.2025.07.005","url":null,"abstract":"<div><h3>Background</h3><div>Limb deformities are almost associated with varying degrees of disability, which severely affects the quality of life and social participation. However, the epidemiological profiles of limb deformities remain underreported. As the world's largest developing country with regional economic disparities, China faces unique challenges in the diagnosis and management of limb deformities. The Qin Sihe Orthopaedic Surgery Database is currently the most comprehensive database of limb deformity in China, which has the largest case volume, the widest disease spectrum, and the broadest geographical coverage, provides an invaluable resource for studying limb deformity patterns in China and other developing countries.</div></div><div><h3>Objective</h3><div>To analyze 37763 limb deformity cases from the Qin Sihe Orthopaedic Surgery Database, and to summarize the etiology distribution, disease spectrum, gender, age, geographical distribution, gait abnormalities and treatment strategies of limb deformities in China.</div></div><div><h3>Methods</h3><div>Descriptive epidemiological methods were used to analyze the data of Qin Sihe Orthopaedic Surgery Database from May 25th, 1978 to December 31st, 2023 containing 37763 cases of Limb deformities. The data on patients' gender, age, etiology distribution, disease spectrum, geographical distribution, gait abnormalities and surgical methods etc will be statistically analyzed.</div></div><div><h3>Results</h3><div>Among 37763 patients, 21815 (57.77 %) were male and 15948 (42.23 %) were female, aged 1–84 years old, covering 33 provinces, municipalities and autonomous regions in China and some international regions. Etiologies included 239 neurogenic, traumatic, congenital and metabolic diseases, among which neurogenic diseases took the dominant portion: 24430 (64. 7 %) cases of post-polio sequelae, 5088 (13. 4 %) cases of cerebral palsy. Lower limb deformities(35,869 cases,95 %) was significantly more than upper limb deformities (646 cases, 1.7 %). The surgical interventions included soft tissue release and tendon lengthening (e. g. Achilles tendon lengthening, 8282 cases, 21.93 %), osteotomy (e.g. supracondylar femoral osteotomy, 7740 cases, 20.50 %), and arthrodesis (e. g. talocalcaneal arthrodesis, 6873 cases, 18.20 %). The fixation methods included Ilizarov external fixation (5611 cases), combined external fixation (5612 cases), combined internal fixation (1805 cases) and plaster or brace immobilization (24735 cases).</div></div><div><h3>Conclusion</h3><div>The causes of limb deformities in China are diverse, and the diseases involves multiple disciplines. Cases are predominantly male and young., Polio sequelae deformity remains the main malformation diseases, but the proportion of cerebral palsy, limb deformities after trauma, lower limb deformities after spina bifida and genetic metabolic diseases are increasing. This study provides important real-world data for the classification of etiol","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 91-100"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687029","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 : 2025-09-01Epub Date: 2025-07-29DOI: 10.1016/j.jot.2025.07.003
Xiaoyu Jin , Xunhao Wang , Siyu Xu , Nuo Xu , Ziwei Wang , Chunqing Hu , Wei Liu , Zhaofeng Zhang , Xiyu Liu , Jingjing Fan , Ruiyang Jiang , Rui Wu , Zhongyang Lv , Dongquan Shi
<div><h3>Background</h3><div>Osteoarthritis (OA) is the most common degenerative joint disease, characterized by cartilage deterioration, which is closely associated with chondrocyte ferroptosis. The aim of this study was to investigate the role and mechanism of previously unexplored gene, growth factor independence 1 (<em>Gfi1</em>) in chondrocyte ferroptosis, in order to provide a new therapeutic target for OA.</div></div><div><h3>Methods</h3><div>The expression of ferroptotic hallmarks and Gfi1 were analyzed in human and mice OA cartilages and tert-butyl hydroperoxide (TBHP)-induced primary chondrocytes. Small interfering RNA or overexpression plasmids were used to knock down or overexpress <em>Gfi1</em> to explore its role in chondrocyte ferroptosis and metabolism. Then, the role of Gfi1 in destabilization of medial meniscus (DMM) surgery-induced mice OA model was investigated with or without the intra-articular injection of adeno-associated virus-overexpressing <em>Gfi1</em> (AAV-<em>Gfi1</em>). Furthermore, RNA sequencing analysis was performed to reveal the key downstream pathway of Gfi1 exerting its role in chondrocyte ferroptosis.</div></div><div><h3>Results</h3><div>The expression of Gfi1 was significantly decreased, while 4-HNE, a typical lipid peroxidation product, was significantly increased both in damaged human and DMM surgery-induced mice OA cartilages. Consistently, Gfi1 was remarkably downregulated in TBHP-induced ferroptotic chondrocytes. Moreover, <em>Gfi1</em> knockdown aggravated chondrocyte ferroptosis by elevated levels of ferroptotic hallmarks, including total ROS, lipid ROS and Fe<sup>2+</sup> accumulation. The upregulation of ferroptotic driver (Cox2, Acsl4) and catabolic marker (Mmp13) and downregulation of ferroptotic suppressors (Gpx4, Fth1, Slc7a11) and anabolic marker (Col II) were also observed in TBHP-induced chondrocytes by <em>Gfi1</em> knockdown. On the contrary, <em>Gfi1</em> overexpression showed anti-ferroptotic effect in TBHP-induced chondrocytes. Intra-articular injection of AAV-<em>Gfi1</em> evidently alleviated cartilage degeneration by resisting ferroptosis and preserving the anabolism-catabolism homeostasis in OA cartilages. Comprehensive evaluation of subchondral bone sclerosis, osteophyte formation, synovitis and behavior performance further validated that <em>Gfi1</em> overexpression ameliorated OA progression. Mechanistically, MAPK signaling pathway was identified as the key downstream mediator of Gfi1 exerting anti-ferroptotic role in OA.</div></div><div><h3>Conclusion</h3><div>Gfi1 is downregulated in OA and its overexpression ameliorates OA progression by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway.</div></div><div><h3>The translational potential of this article</h3><div>This study identifies Gfi1 as a novel therapeutic anti-ferroptotic target for cartilage degeneration, providing more clues for optimizing OA treatment strategies in clinical practice.</div></di
{"title":"Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway","authors":"Xiaoyu Jin , Xunhao Wang , Siyu Xu , Nuo Xu , Ziwei Wang , Chunqing Hu , Wei Liu , Zhaofeng Zhang , Xiyu Liu , Jingjing Fan , Ruiyang Jiang , Rui Wu , Zhongyang Lv , Dongquan Shi","doi":"10.1016/j.jot.2025.07.003","DOIUrl":"10.1016/j.jot.2025.07.003","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is the most common degenerative joint disease, characterized by cartilage deterioration, which is closely associated with chondrocyte ferroptosis. The aim of this study was to investigate the role and mechanism of previously unexplored gene, growth factor independence 1 (<em>Gfi1</em>) in chondrocyte ferroptosis, in order to provide a new therapeutic target for OA.</div></div><div><h3>Methods</h3><div>The expression of ferroptotic hallmarks and Gfi1 were analyzed in human and mice OA cartilages and tert-butyl hydroperoxide (TBHP)-induced primary chondrocytes. Small interfering RNA or overexpression plasmids were used to knock down or overexpress <em>Gfi1</em> to explore its role in chondrocyte ferroptosis and metabolism. Then, the role of Gfi1 in destabilization of medial meniscus (DMM) surgery-induced mice OA model was investigated with or without the intra-articular injection of adeno-associated virus-overexpressing <em>Gfi1</em> (AAV-<em>Gfi1</em>). Furthermore, RNA sequencing analysis was performed to reveal the key downstream pathway of Gfi1 exerting its role in chondrocyte ferroptosis.</div></div><div><h3>Results</h3><div>The expression of Gfi1 was significantly decreased, while 4-HNE, a typical lipid peroxidation product, was significantly increased both in damaged human and DMM surgery-induced mice OA cartilages. Consistently, Gfi1 was remarkably downregulated in TBHP-induced ferroptotic chondrocytes. Moreover, <em>Gfi1</em> knockdown aggravated chondrocyte ferroptosis by elevated levels of ferroptotic hallmarks, including total ROS, lipid ROS and Fe<sup>2+</sup> accumulation. The upregulation of ferroptotic driver (Cox2, Acsl4) and catabolic marker (Mmp13) and downregulation of ferroptotic suppressors (Gpx4, Fth1, Slc7a11) and anabolic marker (Col II) were also observed in TBHP-induced chondrocytes by <em>Gfi1</em> knockdown. On the contrary, <em>Gfi1</em> overexpression showed anti-ferroptotic effect in TBHP-induced chondrocytes. Intra-articular injection of AAV-<em>Gfi1</em> evidently alleviated cartilage degeneration by resisting ferroptosis and preserving the anabolism-catabolism homeostasis in OA cartilages. Comprehensive evaluation of subchondral bone sclerosis, osteophyte formation, synovitis and behavior performance further validated that <em>Gfi1</em> overexpression ameliorated OA progression. Mechanistically, MAPK signaling pathway was identified as the key downstream mediator of Gfi1 exerting anti-ferroptotic role in OA.</div></div><div><h3>Conclusion</h3><div>Gfi1 is downregulated in OA and its overexpression ameliorates OA progression by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway.</div></div><div><h3>The translational potential of this article</h3><div>This study identifies Gfi1 as a novel therapeutic anti-ferroptotic target for cartilage degeneration, providing more clues for optimizing OA treatment strategies in clinical practice.</div></di","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 101-114"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724425","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 : 2025-08-10eCollection Date: 2025-09-01DOI: 10.1016/j.jot.2025.07.011
Yuchen He, Weihong Zhu, Peter G Alexander, Sophie E Hines, Olivia G Bartholomew, Chunfeng Zhao, Qian Liu, Hang Lin
As people age, the progressive loss of cartilage integrity occurs, accompanied by a decline in the capacity to repair. This results in decreased resilience and increased susceptibility of cartilage to various physiological stressors, which raises the risk of developing osteoarthritis (OA). Therefore, restoring the regenerative capacity of chondrocytes and slowing down the aging process could be promising therapeutic strategies to mitigate or even reverse age-related joint diseases. Forkhead box class O (FoxO) proteins are a family of transcription factors that play a crucial role in various cellular processes linked to aging. Their significant functions in cell cycle regulation, apoptosis, and resistance to oxidative stress highlight their importance in maintaining cellular homeostasis and promoting longevity. In this review, we introduce the structures and functions of FoxO proteins in chondrocytes, focusing on their spatiotemporal regulation of epigenetics during chondrocyte differentiation stages in different layers. The critical roles of FoxO proteins in maintaining chondrocyte homeostasis are summarized, alongside a discussion of how FoxO dysfunction contributes to aging and OA. Furthermore, therapeutic strategies targeting FoxO proteins to mitigate aging-related cartilage degradation and decelerate OA progression are explored. Finally, potential directions for future research are proposed to deepen the current understanding of FoxO proteins.
The translational potential of this article: FoxO transcription factors, especially FoxO1 and FoxO3, are promising therapeutic targets for promoting longevity, stimulating cartilage regeneration, and treating aging-related diseases like OA.
{"title":"Forkhead box O proteins in chondrocyte aging and diseases.","authors":"Yuchen He, Weihong Zhu, Peter G Alexander, Sophie E Hines, Olivia G Bartholomew, Chunfeng Zhao, Qian Liu, Hang Lin","doi":"10.1016/j.jot.2025.07.011","DOIUrl":"10.1016/j.jot.2025.07.011","url":null,"abstract":"<p><p>As people age, the progressive loss of cartilage integrity occurs, accompanied by a decline in the capacity to repair. This results in decreased resilience and increased susceptibility of cartilage to various physiological stressors, which raises the risk of developing osteoarthritis (OA). Therefore, restoring the regenerative capacity of chondrocytes and slowing down the aging process could be promising therapeutic strategies to mitigate or even reverse age-related joint diseases. Forkhead box class O (FoxO) proteins are a family of transcription factors that play a crucial role in various cellular processes linked to aging. Their significant functions in cell cycle regulation, apoptosis, and resistance to oxidative stress highlight their importance in maintaining cellular homeostasis and promoting longevity. In this review, we introduce the structures and functions of FoxO proteins in chondrocytes, focusing on their spatiotemporal regulation of epigenetics during chondrocyte differentiation stages in different layers. The critical roles of FoxO proteins in maintaining chondrocyte homeostasis are summarized, alongside a discussion of how FoxO dysfunction contributes to aging and OA. Furthermore, therapeutic strategies targeting FoxO proteins to mitigate aging-related cartilage degradation and decelerate OA progression are explored. Finally, potential directions for future research are proposed to deepen the current understanding of FoxO proteins.</p><p><strong>The translational potential of this article: </strong>FoxO transcription factors, especially FoxO1 and FoxO3, are promising therapeutic targets for promoting longevity, stimulating cartilage regeneration, and treating aging-related diseases like OA.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"167-179"},"PeriodicalIF":5.9,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-09eCollection Date: 2025-09-01DOI: 10.1016/j.jot.2025.07.012
Fen Miao, Hanjia Cai, Yue Chen, Ziwei Yan, Ruofan Jin, Yueming Dai, Lu Li, Hua Wang, Yan Xu, Wen Sun
Objective: Rheumatoid arthritis (RA) is often characterized by bone loss and fragility fractures and is a frequent comorbidity. The NLRP3 inflammasome drives inflammatory processes that fundamentally accompany the pathogenesis of RA. However, the role of NLRP3 inflammasome in RA fracture healing remains unclear.
Methods: For in vivo analyses, we established tibial fractures in two murine RA models: TNF-transgenic (TNFTg) mice and collagen-induced arthritis (CIA). To address the contribution of NLRP3 inflammasome to fracture repair, we generated TNFTg; NLRP3KO mice by deleting the NLRP3 gene in TNFTg mice. The effects of TNFα overexpression on osteogenic differentiation were assessed using mesenchymal progenitor cells (MPCs) with or without MCC950. The role of MCC950 in RA fracture repair was investigated using CIA mice.
Results: TNFTg mice exhibited delayed fracture healing, characterized by decreased callus bone volume and reduced bone mechanical strength. The NLRP3 inflammasome was excessively activated in TNFTg mice, leading to elevated expression of NLRP3, pro-Caspase-1, Caspase-1 p20, pro-IL-1β and IL-1β. Moreover, NLRP3 deficiency in TNFTg mice significantly mitigated the delayed fracture healing. Mechanistically, TNFα overexpression suppressed osteogenic differentiation of MPCs through NLRP3 inflammasome activation. This process involves RhoA/Rac1-dependent NF-κB signaling that triggers inflammasome assembly, ultimately leading to IL-1β secretion. Notably, MCC950 administration significantly attenuated these pathological effects. Lastly, in vivo MCC950 treatment rescued the delayed fracture healing by reducing NLRP3 inflammasome activation and promoting bone formation in CIA mice.
Conclusions: Collectively, these findings suggest that NLRP3 inflammasome activation drives impaired fracture healing in RA through RhoA/Rac1‒IL-1β axis-mediated suppression of osteoblast differentiation, and pharmacologic inhibition with MCC950 effectively rescues delayed fracture healing in RA mouse model.
The translational potential of this article: This study provides novel insights into the mechanisms underlying delayed fracture healing in RA and highlights the potential therapeutic benefits of targeting the NLRP3 inflammasome.
{"title":"NLRP3 inflammasome impairs fracture repair in Rheumatoid arthritis through RhoA/Rac1-IL1β axis-mediated suppression of osteoblast differentiation.","authors":"Fen Miao, Hanjia Cai, Yue Chen, Ziwei Yan, Ruofan Jin, Yueming Dai, Lu Li, Hua Wang, Yan Xu, Wen Sun","doi":"10.1016/j.jot.2025.07.012","DOIUrl":"10.1016/j.jot.2025.07.012","url":null,"abstract":"<p><strong>Objective: </strong>Rheumatoid arthritis (RA) is often characterized by bone loss and fragility fractures and is a frequent comorbidity. The NLRP3 inflammasome drives inflammatory processes that fundamentally accompany the pathogenesis of RA. However, the role of NLRP3 inflammasome in RA fracture healing remains unclear.</p><p><strong>Methods: </strong>For <i>in vivo</i> analyses, we established tibial fractures in two murine RA models: TNF-transgenic (TNF<sup>Tg</sup>) mice and collagen-induced arthritis (CIA). To address the contribution of NLRP3 inflammasome to fracture repair, we generated TNF<sup>Tg</sup>; NLRP3<sup>KO</sup> mice by deleting the NLRP3 gene in TNF<sup>Tg</sup> mice. The effects of TNFα overexpression on osteogenic differentiation were assessed using mesenchymal progenitor cells (MPCs) with or without MCC950. The role of MCC950 in RA fracture repair was investigated using CIA mice.</p><p><strong>Results: </strong>TNF<sup>Tg</sup> mice exhibited delayed fracture healing, characterized by decreased callus bone volume and reduced bone mechanical strength. The NLRP3 inflammasome was excessively activated in TNF<sup>Tg</sup> mice, leading to elevated expression of NLRP3, pro-Caspase-1, Caspase-1 p20, pro-IL-1β and IL-1β. Moreover, NLRP3 deficiency in TNF<sup>Tg</sup> mice significantly mitigated the delayed fracture healing. Mechanistically, TNFα overexpression suppressed osteogenic differentiation of MPCs through NLRP3 inflammasome activation. This process involves RhoA/Rac1-dependent NF-κB signaling that triggers inflammasome assembly, ultimately leading to IL-1β secretion. Notably, MCC950 administration significantly attenuated these pathological effects. Lastly, <i>in vivo</i> MCC950 treatment rescued the delayed fracture healing by reducing NLRP3 inflammasome activation and promoting bone formation in CIA mice.</p><p><strong>Conclusions: </strong>Collectively, these findings suggest that NLRP3 inflammasome activation drives impaired fracture healing in RA through RhoA/Rac1‒IL-1β axis-mediated suppression of osteoblast differentiation, and pharmacologic inhibition with MCC950 effectively rescues delayed fracture healing in RA mouse model.</p><p><strong>The translational potential of this article: </strong>This study provides novel insights into the mechanisms underlying delayed fracture healing in RA and highlights the potential therapeutic benefits of targeting the NLRP3 inflammasome.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"152-166"},"PeriodicalIF":5.9,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In the last two decades, technological interventions have played a significant role in transforming healthcare with timely diagnosis and novel therapeutic interventions. Advanced technologies such as next-generation sequencing, NMR, mass spectrometry, and non-invasive imaging modalities have made it possible to study biological molecules, cellular processes, and molecular pathways in different diseases. The "omics revolution" is another addition that emerged as a powerful tool in elucidating molecular and cellular processes in diseases. Given the profoundly complex nature of tissue repair, it is important to employ the advanced multi-omics technique to elucidate the cellular, molecular, and inflammatory events in damaged tissues. As proven in various other diseases, these integrative omics can provide a systematic and comprehensive understanding of the biology of tissue repair and regeneration. Proteomics and transcriptomics, in particular, have been widely used for the identification and validation of potential biomarkers such as transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and several matrix metalloproteinases (MMPs) which play a key role in the process of tissue repair and regeneration. Metabolomics, such as NMR and spectroscopies, have also shown potential in tracking energy metabolism and oxidative stress during regeneration. This review article presents a comprehensive overview of the latest multi-omics techniques and technologies that provide valuable insights into the complex processes of tissue repair and highlight the possibilities of early diagnosis, biomarker identification, and novel therapeutic interventions for tissue repair and regeneration. Combining data and key findings from multiple omics layers, such as metabolomics, transcriptomics, and genomics, may provide a comprehensive understanding of the mechanisms and pathways that have been implicated in tissue repair and regeneration. This may lead to the identification and validation of robust biomarkers and the development of therapeutic strategies aimed at improving outcomes in patients with chronic and non-healing wounds.
The translational potential of this article: This article reviews the application of multi-omics technologies in tissue repair and regeneration, highlighting how the integration of genomics, transcriptomics, proteomics, and metabolomics reveals molecular mechanisms of wound healing. By combining these diverse omics approaches, the findings provide critical insights into novel biomarkers, therapeutic targets, and personalized treatment strategies. This integration allows for a more comprehensive understanding of tissue regeneration, enhancing diagnostic accuracy and treatment monitoring. Ultimately, multi-omics technologies can drive advances in personalized medicine, improving clinical outcomes and offering new avenues for treating tissue repair and regeneration.
{"title":"The role of multi-omics in biomarker discovery, diagnosis, prognosis, and therapeutic monitoring of tissue repair and regeneration processes.","authors":"Jiamei Liu, Liyu Yang, Dongze Liu, Qianlong Wu, Yuanqi Yu, Xiaoming Huang, Jianjun Li, Shengye Liu","doi":"10.1016/j.jot.2025.07.006","DOIUrl":"10.1016/j.jot.2025.07.006","url":null,"abstract":"<p><p>In the last two decades, technological interventions have played a significant role in transforming healthcare with timely diagnosis and novel therapeutic interventions. Advanced technologies such as next-generation sequencing, NMR, mass spectrometry, and non-invasive imaging modalities have made it possible to study biological molecules, cellular processes, and molecular pathways in different diseases. The \"omics revolution\" is another addition that emerged as a powerful tool in elucidating molecular and cellular processes in diseases. Given the profoundly complex nature of tissue repair, it is important to employ the advanced multi-omics technique to elucidate the cellular, molecular, and inflammatory events in damaged tissues. As proven in various other diseases, these integrative omics can provide a systematic and comprehensive understanding of the biology of tissue repair and regeneration. Proteomics and transcriptomics, in particular, have been widely used for the identification and validation of potential biomarkers such as transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and several matrix metalloproteinases (MMPs) which play a key role in the process of tissue repair and regeneration. Metabolomics, such as NMR and spectroscopies, have also shown potential in tracking energy metabolism and oxidative stress during regeneration. This review article presents a comprehensive overview of the latest multi-omics techniques and technologies that provide valuable insights into the complex processes of tissue repair and highlight the possibilities of early diagnosis, biomarker identification, and novel therapeutic interventions for tissue repair and regeneration. Combining data and key findings from multiple omics layers, such as metabolomics, transcriptomics, and genomics, may provide a comprehensive understanding of the mechanisms and pathways that have been implicated in tissue repair and regeneration. This may lead to the identification and validation of robust biomarkers and the development of therapeutic strategies aimed at improving outcomes in patients with chronic and non-healing wounds.</p><p><strong>The translational potential of this article: </strong>This article reviews the application of multi-omics technologies in tissue repair and regeneration, highlighting how the integration of genomics, transcriptomics, proteomics, and metabolomics reveals molecular mechanisms of wound healing. By combining these diverse omics approaches, the findings provide critical insights into novel biomarkers, therapeutic targets, and personalized treatment strategies. This integration allows for a more comprehensive understanding of tissue regeneration, enhancing diagnostic accuracy and treatment monitoring. Ultimately, multi-omics technologies can drive advances in personalized medicine, improving clinical outcomes and offering new avenues for treating tissue repair and regeneration.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"131-151"},"PeriodicalIF":5.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Inflammatory arthritis (IA), exemplified by rheumatoid arthritis (RA), represents a prevalent autoimmune-driven inflammatory bone disorder hallmarked by chronic synovitis and progressive bone erosion, culminating in joint dysfunction and systemic osteoporosis. Narirutin (NRT), a flavonoid glycoside derived from citrus plants, is renowned for its multifaceted bioactivities, including antioxidant, immunomodulatory, and cardioprotective properties. Despite these attributes, the role of NRT in mitigating macrophage-mediated pro-inflammatory activation and osteoclastogenesis within the context of inflammatory arthritis and osteoporosis remains insufficiently elucidated. This study aimed to evaluate the therapeutic potential of NRT in the context of inflammatory arthritis and osteoporosis.
Methods: The phenotypic modulation of macrophages and the osteoclastogenic effects of NRT were evaluated using RAW264.7, THP-1 and bone marrow-derived macrophages (BMMs) in vitro. A classical collagen-induced arthritis (CIA) model was established to investigate the therapeutic effects of NRT administration on inflammatory arthritis and osteoporosis. Macrophage phenotypes and the expression of inflammatory mediators were analyzed in vitro and vivo, respectively. High-throughput RNA sequencing and bioinformatics analyses were employed to identify key downstream signaling pathways, which were further validated. Histological staining, micro-CT, and immunehistofluorescence staining were utilized to assess the in vivo amelioration of inflammation and bone destruction. Visceral toxicity was also assessed in vivo.
Results: NRT markedly inhibited lipopolysaccharide (LPS)-induced macrophage polarization towards the pro-inflammatory M1 phenotype (CD86+), while promoting a shift towards the anti-inflammatory M2 phenotype (CD206+). This was accompanied by a suppression of pro-inflammatory cytokines, including iNOS, TNF, IL-1β, and IL-6, and an upregulation of immunosuppressive mediators such as IL-10 and Arg-1. RNA sequencing revealed that NRT attenuates the activation of the NOD-like receptor signaling pathway and downstream inflammasome activation. Additionally, osteoclast differentiation was also significantly inhibited, as evidenced by the suppression of NF-κB and MAPK signaling pathways. In vivo studies demonstrated that NRT substantially alleviates the severity of inflammatory arthritis and mitigates systemic osteoporosis.
Conclusion: These findings demonstrated that NRT mitigates inflammatory arthritis and osteoporosis through modulating macrophage phenotype and osteoclastogenesis via NOD-like receptor signaling pathway induced inflammasome activation and NF-κB and MAPK signaling pathways, respectively.
The translational potential of this article: These findings highlight the potential of tar
{"title":"Narirutin mitigates inflammatory arthritis and osteoporosis through modulating macrophage phenotype and osteoclastogenesis.","authors":"Qing Wang, Xiaole Peng, Hao Xu, Yuhu Zhao, Xiaoheng Lu, Chengyao Lu, Qihan Wang, Wei Lu, Qifeng Sheng, Xiaomin Lu, Yaozeng Xu, Dechun Geng","doi":"10.1016/j.jot.2025.07.008","DOIUrl":"10.1016/j.jot.2025.07.008","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory arthritis (IA), exemplified by rheumatoid arthritis (RA), represents a prevalent autoimmune-driven inflammatory bone disorder hallmarked by chronic synovitis and progressive bone erosion, culminating in joint dysfunction and systemic osteoporosis. Narirutin (NRT), a flavonoid glycoside derived from citrus plants, is renowned for its multifaceted bioactivities, including antioxidant, immunomodulatory, and cardioprotective properties. Despite these attributes, the role of NRT in mitigating macrophage-mediated pro-inflammatory activation and osteoclastogenesis within the context of inflammatory arthritis and osteoporosis remains insufficiently elucidated. This study aimed to evaluate the therapeutic potential of NRT in the context of inflammatory arthritis and osteoporosis.</p><p><strong>Methods: </strong>The phenotypic modulation of macrophages and the osteoclastogenic effects of NRT were evaluated using RAW264.7, THP-1 and bone marrow-derived macrophages (BMMs) <i>in vitro</i>. A classical collagen-induced arthritis (CIA) model was established to investigate the therapeutic effects of NRT administration on inflammatory arthritis and osteoporosis. Macrophage phenotypes and the expression of inflammatory mediators were analyzed <i>in vitro</i> and <i>vivo</i>, respectively. High-throughput RNA sequencing and bioinformatics analyses were employed to identify key downstream signaling pathways, which were further validated. Histological staining, micro-CT, and immunehistofluorescence staining were utilized to assess the <i>in vivo</i> amelioration of inflammation and bone destruction. Visceral toxicity was also assessed <i>in vivo</i>.</p><p><strong>Results: </strong>NRT markedly inhibited lipopolysaccharide (LPS)-induced macrophage polarization towards the pro-inflammatory M1 phenotype (CD86<sup>+</sup>), while promoting a shift towards the anti-inflammatory M2 phenotype (CD206+). This was accompanied by a suppression of pro-inflammatory cytokines, including iNOS, TNF, IL-1β, and IL-6, and an upregulation of immunosuppressive mediators such as IL-10 and Arg-1. RNA sequencing revealed that NRT attenuates the activation of the NOD-like receptor signaling pathway and downstream inflammasome activation. Additionally, osteoclast differentiation was also significantly inhibited, as evidenced by the suppression of NF-κB and MAPK signaling pathways. <i>In vivo</i> studies demonstrated that NRT substantially alleviates the severity of inflammatory arthritis and mitigates systemic osteoporosis.</p><p><strong>Conclusion: </strong>These findings demonstrated that NRT mitigates inflammatory arthritis and osteoporosis through modulating macrophage phenotype and osteoclastogenesis <i>via</i> NOD-like receptor signaling pathway induced inflammasome activation and NF-κB and MAPK signaling pathways, respectively.</p><p><strong>The translational potential of this article: </strong>These findings highlight the potential of tar","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"115-130"},"PeriodicalIF":5.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-05-28DOI: 10.1016/j.jot.2025.05.001
Qiuyuan Wang , Moli Huang , Jiong Jiong Guo
Single-cell RNA sequencing (scRNA-seq) technology hold significant potential for advancing orthopedic research. This review examines the impact of ScRNA-seq on the future development of orthopedic research and practice. In the study of osteoarthritis, scRNA-seq can finely characterize the changes in the subsets of chondrocytes and their role in disease progression. In rheumatoid arthritis, this technique reveals the complex heterogeneity and cell-to-cell interactions between fibroblasts and immune cells. ScRNA-seq offers insights into the heterogeneity of nucleus pulposus, annulus fibrosus, and endplate cells, providing a novel perspective on the pathological mechanisms of intervertebral disc degeneration. Single-cell analysis in osteosarcoma research has uncovered the complexity of the tumor microenvironment and mechanisms of immunosuppression. Through these studies, scRNA-seq enhances insights into disease pathogenesis and offers innoviate approaches for precision medicine and personalized treatment strategies.
The Translational Potential of this Article
This article systematically reviews the cellular heterogeneity, molecular mechanisms and immune microenvironment of orthopedic diseases (such as osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteosarcoma) by single-cell RNA sequencing (scRNA-seq), which provides a theoretical basis for accurate diagnosis, new therapeutic target discovery (such as TRPV1, CXCR4) and individualized treatment strategies. The combination of multi-omics and spatial transcriptome technology is expected to accelerate clinical translation and optimize the diagnosis and treatment system of orthopedic diseases.
{"title":"From cells to clinic: Single-cell transcriptomics shaping the future of orthopedics","authors":"Qiuyuan Wang , Moli Huang , Jiong Jiong Guo","doi":"10.1016/j.jot.2025.05.001","DOIUrl":"10.1016/j.jot.2025.05.001","url":null,"abstract":"<div><div>Single-cell RNA sequencing (scRNA-seq) technology hold significant potential for advancing orthopedic research. This review examines the impact of ScRNA-seq on the future development of orthopedic research and practice. In the study of osteoarthritis, scRNA-seq can finely characterize the changes in the subsets of chondrocytes and their role in disease progression. In rheumatoid arthritis, this technique reveals the complex heterogeneity and cell-to-cell interactions between fibroblasts and immune cells. ScRNA-seq offers insights into the heterogeneity of nucleus pulposus, annulus fibrosus, and endplate cells, providing a novel perspective on the pathological mechanisms of intervertebral disc degeneration. Single-cell analysis in osteosarcoma research has uncovered the complexity of the tumor microenvironment and mechanisms of immunosuppression. Through these studies, scRNA-seq enhances insights into disease pathogenesis and offers innoviate approaches for precision medicine and personalized treatment strategies.</div></div><div><h3>The Translational Potential of this Article</h3><div>This article systematically reviews the cellular heterogeneity, molecular mechanisms and immune microenvironment of orthopedic diseases (such as osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteosarcoma) by single-cell RNA sequencing (scRNA-seq), which provides a theoretical basis for accurate diagnosis, new therapeutic target discovery (such as TRPV1, CXCR4) and individualized treatment strategies. The combination of multi-omics and spatial transcriptome technology is expected to accelerate clinical translation and optimize the diagnosis and treatment system of orthopedic diseases.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 1-11"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155084","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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