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 : 2025-07-29DOI: 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":"2025-07-29","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 : 2025-07-23DOI: 10.1016/j.jot.2025.07.002
Shen Liu , Tingmo Huang , Liyang Wan , Yinghong Xiong , Liyue Zeng , Ruixue Du , Ziyang Lin , Zilong Guo , Hongbin Lu , Daqi Xu
Background
Rotator cuff injury (RCI) often leads to chronic pain and anxiety, yet the underlying neural mechanisms remain unclear. This study explored central mechanisms linking RCI to these symptoms and assessed treadmill exercise (TE) as a therapeutic intervention in mice.
Methods
Male C57BL/6 mice underwent RCI surgery and were randomized into Sham, RCI, or TE groups (TE initiated on postoperative day 7). Mechanical hypersensitivity and anxiety-like behaviors were evaluated via von Frey, elevated plus maze, and open field tests. Synaptic plasticity proteins and structures in the paraventricular nucleus (PVN) were analyzed using immunofluorescence, Western blotting, electron microscopy, and Golgi staining. The brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) pathway's role was tested using the TrkB inhibitor ANA-12.
Results
RCI elicited notable alterations in synaptic structure within the PVN, characterized by decreased synaptophysin expression, increased growth-associated protein 43 expression, and synaptic microstructural abnormalities. These synaptic modifications were correlated with the manifestation of hyperalgesia and anxiety-like behaviors in murine models. TE reversed these synaptic changes and improved pain and anxiety symptoms. Mechanistically, TE activated the BDNF-TrkB signaling pathway in the PVN, which was essential for its therapeutic effects. Pharmacological blockade of the TrkB receptor using ANA-12 attenuated the therapeutic benefits of TE, confirming the critical role of BDNF-TrkB signaling pathway.
Conclusion
TE mitigates RCI-related pain and anxiety by restoring PVN synaptic plasticity via BDNF-TrkB signaling, underscoring exercise's therapeutic potential.
The translational potential of this article
The study reveals new insights into the central neural mechanisms of pain and anxiety after RCI, highlighting synaptic plasticity changes in the PVN. It clarifies the link between peripheral injury and central nervous system alterations, guiding clinicians toward more targeted and effective treatments.
{"title":"The effects of exercise on pain and anxiety following rotator cuff injury: the role of paraventricular nucleus synaptic plasticity","authors":"Shen Liu , Tingmo Huang , Liyang Wan , Yinghong Xiong , Liyue Zeng , Ruixue Du , Ziyang Lin , Zilong Guo , Hongbin Lu , Daqi Xu","doi":"10.1016/j.jot.2025.07.002","DOIUrl":"10.1016/j.jot.2025.07.002","url":null,"abstract":"<div><h3>Background</h3><div>Rotator cuff injury (RCI) often leads to chronic pain and anxiety, yet the underlying neural mechanisms remain unclear. This study explored central mechanisms linking RCI to these symptoms and assessed treadmill exercise (TE) as a therapeutic intervention in mice.</div></div><div><h3>Methods</h3><div>Male C57BL/6 mice underwent RCI surgery and were randomized into Sham, RCI, or TE groups (TE initiated on postoperative day 7). Mechanical hypersensitivity and anxiety-like behaviors were evaluated via von Frey, elevated plus maze, and open field tests. Synaptic plasticity proteins and structures in the paraventricular nucleus (PVN) were analyzed using immunofluorescence, Western blotting, electron microscopy, and Golgi staining. The brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) pathway's role was tested using the TrkB inhibitor ANA-12.</div></div><div><h3>Results</h3><div>RCI elicited notable alterations in synaptic structure within the PVN, characterized by decreased synaptophysin expression, increased growth-associated protein 43 expression, and synaptic microstructural abnormalities. These synaptic modifications were correlated with the manifestation of hyperalgesia and anxiety-like behaviors in murine models. TE reversed these synaptic changes and improved pain and anxiety symptoms. Mechanistically, TE activated the BDNF-TrkB signaling pathway in the PVN, which was essential for its therapeutic effects. Pharmacological blockade of the TrkB receptor using ANA-12 attenuated the therapeutic benefits of TE, confirming the critical role of BDNF-TrkB signaling pathway.</div></div><div><h3>Conclusion</h3><div>TE mitigates RCI-related pain and anxiety by restoring PVN synaptic plasticity via BDNF-TrkB signaling, underscoring exercise's therapeutic potential.</div></div><div><h3>The translational potential of this article</h3><div>The study reveals new insights into the central neural mechanisms of pain and anxiety after RCI, highlighting synaptic plasticity changes in the PVN. It clarifies the link between peripheral injury and central nervous system alterations, guiding clinicians toward more targeted and effective treatments.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 77-90"},"PeriodicalIF":5.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686372","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 : 2025-07-23DOI: 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":"2025-07-23","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 : 2025-07-22DOI: 10.1016/j.jot.2025.03.012
W.X. Tong, H.J. Chen, Z.L. Huang, D. Zhao, J. Hu
Background
Osteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. The Wnt/β-catenin cascade is essential in articular cartilage development and homeostasis. Interruption of β-catenin (either overexpression or inhibition) leads to cartilage degeneration. However, the mechanism for stabilizing Wnt/β-catenin remains unclear.
Methods
We established the mouse destabilization of the medial meniscus (DMM) OA model and analyzed the clinical specimens to detect Wnt/β-catenin and PTHrP. The chondrocytes were isolated and treated with various cytokines including Wnt3a, Ihh, IL-1β, and PTHrP to reveal the molecular mechanism. Epigenetic and bioinformatic analyses were conducted to screen the key genes for the PTHrP regulation, and an Adeno-associated Virus (AAV) delivery system for PTHrP was established for OA gene therapy (prevention) application.
Results
We confirmed the Wnt/β-catenin activation and PTHrP suppression in cartilage in post-traumatic OA. Wnt/β-catenin further upregulated PTHrP expression through binding to its promoter (P2), and induced mRNA (AT6) transcript expression. Unexpectedly, PTHrP repressed Wnt/β-catenin activity and formed a Wnt/β-catenin-PTHrP negative feedback loop in very primary chondrocytes to maintain cartilage homeostasis. However, this negative feedback loop vanished in dedifferentiated chondrocytes, hypertrophic chondrocytes, and IL-1β treated primary chondrocytes. In these chondrocytes under pathological conditions, we further found that miR-106b-5p was increased and directly targeted PTHrP mRNA to abolish the feedback loop. Using Bulk RNA-seq and KEGG analysis, we screened and confirmed that PKC-ζ was activated by PTHrP through phosphorylation at Thr410/403, and subsequently induced β-catenin phosphorylation, ubiquitination and degeneration. Finally, we disclosed that exogenous PTHrP attenuated OA progression.
Conclusion
This study reveals that PTHrP is a vital mediator in keeping Wnt/β-catenin homeostasis through a negative feedback loop similar to its role in balancing the Ihh pathway activity in the secondary ossification center and growth plate.
The translational potential of this article
These findings highlight that PTHrP might be a therapeutic target for attenuating cartilage degeneration and OA process by the gene therapy approach.
{"title":"PTHrP buffers Wnt/β-catenin activity through a PKC-ζ involved negative feedback loop to maintain articular cartilage homeostasis and attenuate osteoarthritis","authors":"W.X. Tong, H.J. Chen, Z.L. Huang, D. Zhao, J. Hu","doi":"10.1016/j.jot.2025.03.012","DOIUrl":"10.1016/j.jot.2025.03.012","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. The Wnt/β-catenin cascade is essential in articular cartilage development and homeostasis. Interruption of β-catenin (either overexpression or inhibition) leads to cartilage degeneration. However, the mechanism for stabilizing Wnt/β-catenin remains unclear.</div></div><div><h3>Methods</h3><div>We established the mouse destabilization of the medial meniscus (DMM) OA model and analyzed the clinical specimens to detect Wnt/β-catenin and PTHrP. The chondrocytes were isolated and treated with various cytokines including Wnt3a, Ihh, IL-1β, and PTHrP to reveal the molecular mechanism. Epigenetic and bioinformatic analyses were conducted to screen the key genes for the PTHrP regulation, and an Adeno-associated Virus (AAV) delivery system for PTHrP was established for OA gene therapy (prevention) application.</div></div><div><h3>Results</h3><div>We confirmed the Wnt/β-catenin activation and PTHrP suppression in cartilage in post-traumatic OA. Wnt/β-catenin further upregulated PTHrP expression through binding to its promoter (P2), and induced mRNA (AT6) transcript expression. Unexpectedly, PTHrP repressed Wnt/β-catenin activity and formed a Wnt/β-catenin-PTHrP negative feedback loop in very primary chondrocytes to maintain cartilage homeostasis. However, this negative feedback loop vanished in dedifferentiated chondrocytes, hypertrophic chondrocytes, and IL-1β treated primary chondrocytes. In these chondrocytes under pathological conditions, we further found that miR-106b-5p was increased and directly targeted PTHrP mRNA to abolish the feedback loop. Using Bulk RNA-seq and KEGG analysis, we screened and confirmed that PKC-ζ was activated by PTHrP through phosphorylation at Thr410/403, and subsequently induced β-catenin phosphorylation, ubiquitination and degeneration. Finally, we disclosed that exogenous PTHrP attenuated OA progression.</div></div><div><h3>Conclusion</h3><div>This study reveals that PTHrP is a vital mediator in keeping Wnt/β-catenin homeostasis through a negative feedback loop similar to its role in balancing the Ihh pathway activity in the secondary ossification center and growth plate.</div></div><div><h3>The translational potential of this article</h3><div>These findings highlight that PTHrP might be a therapeutic target for attenuating cartilage degeneration and OA process by the gene therapy approach.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 65-76"},"PeriodicalIF":5.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679134","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 : 2025-07-17DOI: 10.1016/j.jot.2025.06.016
Serban Dragosloveanu , Diana Elena Vulpe , Constantin Adrian Andrei , Dana-Georgiana Nedelea , Nicolae Dragos Garofil , Cătălin Anghel , Christiana Diana Maria Dragosloveanu , Romica Cergan , Cristian Scheau
Background and objectives
Periprosthetic joint infection (PJI) is a serious complication that can occur after joint arthroplasty, such as hip or knee replacement surgeries. It involves the invasion of the periprosthetic space by pathogens, leading to severe inflammation and often requiring complex medical intervention. PJI is associated with significant morbidity, increased healthcare costs, and a reduced quality of life for patients. This study aims to evaluate the performance of multiple supervised machine learning models in predicting PJI using clinical and demographic data collected from patients who underwent joint arthroplasty.
Methods
Eight supervised machine learning models—Logistic Regression, Random Forest, XGBoost, Artificial Neural Network (ANN), k-Nearest Neighbors (KNN), AdaBoost, Gaussian Naive Bayes (GNB), and Stochastic Gradient Descent (SGD)—were trained and tested on a dataset of 27,854 patients. Models were evaluated using accuracy, precision, recall, specificity, F1 score, and area under the ROC curve (AUC).
Results
Random Forest and XGBoost showed the best overall performance, with high accuracy and balanced metrics across all evaluation criteria. KNN also performed strongly, particularly in minimizing misclassifications. GNB and SGD yielded weaker results, with higher error rates.
Conclusion
Random Forest, XGBoost, and KNN are the most promising models for clinical implementation in PJI prediction. Their robust performance may support earlier diagnosis and improved patient outcomes in orthopedic care.
Translational potential statement
This study demonstrates that machine learning models—particularly Random Forest and XGBoost—can accurately predict periprosthetic joint infection (PJI) using structured electronic health record data. By integrating these models into preoperative assessment workflows, clinicians may be able to identify high-risk patients earlier, personalize prophylactic strategies, and reduce infection-related morbidity. The implementation of these predictive tools has the potential to enhance clinical decision-making, improve surgical outcomes, and optimize the use of healthcare resources in orthopedic practice.
{"title":"Predicting periprosthetic joint Infection: Evaluating supervised machine learning models for clinical application","authors":"Serban Dragosloveanu , Diana Elena Vulpe , Constantin Adrian Andrei , Dana-Georgiana Nedelea , Nicolae Dragos Garofil , Cătălin Anghel , Christiana Diana Maria Dragosloveanu , Romica Cergan , Cristian Scheau","doi":"10.1016/j.jot.2025.06.016","DOIUrl":"10.1016/j.jot.2025.06.016","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Periprosthetic joint infection (PJI) is a serious complication that can occur after joint arthroplasty, such as hip or knee replacement surgeries. It involves the invasion of the periprosthetic space by pathogens, leading to severe inflammation and often requiring complex medical intervention. PJI is associated with significant morbidity, increased healthcare costs, and a reduced quality of life for patients. This study aims to evaluate the performance of multiple supervised machine learning models in predicting PJI using clinical and demographic data collected from patients who underwent joint arthroplasty.</div></div><div><h3>Methods</h3><div>Eight supervised machine learning models—Logistic Regression, Random Forest, XGBoost, Artificial Neural Network (ANN), k-Nearest Neighbors (KNN), AdaBoost, Gaussian Naive Bayes (GNB), and Stochastic Gradient Descent (SGD)—were trained and tested on a dataset of 27,854 patients. Models were evaluated using accuracy, precision, recall, specificity, F1 score, and area under the ROC curve (AUC).</div></div><div><h3>Results</h3><div>Random Forest and XGBoost showed the best overall performance, with high accuracy and balanced metrics across all evaluation criteria. KNN also performed strongly, particularly in minimizing misclassifications. GNB and SGD yielded weaker results, with higher error rates.</div></div><div><h3>Conclusion</h3><div>Random Forest, XGBoost, and KNN are the most promising models for clinical implementation in PJI prediction. Their robust performance may support earlier diagnosis and improved patient outcomes in orthopedic care.</div></div><div><h3>Translational potential statement</h3><div>This study demonstrates that machine learning models—particularly Random Forest and XGBoost—can accurately predict periprosthetic joint infection (PJI) using structured electronic health record data. By integrating these models into preoperative assessment workflows, clinicians may be able to identify high-risk patients earlier, personalize prophylactic strategies, and reduce infection-related morbidity. The implementation of these predictive tools has the potential to enhance clinical decision-making, improve surgical outcomes, and optimize the use of healthcare resources in orthopedic practice.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 51-64"},"PeriodicalIF":5.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653082","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 : 2025-07-16DOI: 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":"2025-07-16","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号