Pub Date : 2025-04-29DOI: 10.1016/j.jot.2025.04.001
Yechao Shen , Boren Tan , Jiahao Zhang , Ning Zhang , Zhan Wang
<div><h3>Background</h3><div>Fractures are a significant global public health concern, imposing a substantial economic burden, particularly among the elderly. However, research on the fracture burden in Asia remains limited, highlighting the need for comprehensive and up-to-date studies to support the effective planning and allocation of healthcare resources across the region.</div></div><div><h3>Methods</h3><div>Using the Global Burden of Disease (GBD) 2021 database, we analyzed the age-standardized rates (ASRs) of incidence (ASIR), prevalence (ASPR), and years lived with disability (YLDs) (ASYR) associated with fracture burden across Asia. Our study explored trends over time, variations by age, sex, and country, and examined the correlation between fracture burden and the sociodemographic index (SDI).</div></div><div><h3>Results</h3><div>In 2021, fractures in Asia caused 91.3 million (95 % uncertainty interval, 83.65–99.47) incident cases, 232.71 million (95 % UI, (215.57–250.39) prevalent cases, and 12.97 million (95 % UI, 8.89–17.82) YLDs, with age-standardized rates of 1968.49 (95 % UI, 1799.15–2147.14) for incidence (ASIR), 4683.96 (95 % UI, 4347.58–5036.61) for prevalence (ASPR), and 261.72 (95 % UI, 179.43–358.94) for YLDs (ASYR) per 100,000 population. Despite a higher absolute burden, Asian age-standardized rates of fracture were slightly lower than the global average. For ASYR, the most burdensome fractures were those of the patella, tibia/fibula/ankle, hip, and pelvis. Between 1990 and 2021, fracture incident cases, prevalent cases, and YLDs in Asia increased markedly. Age and sex differences were observed, with the elderly experiencing the highest fracture burden, particularly for hip fractures in women. While men had a higher overall fracture burden, women faced a greater fracture disease burden in the elderly population. Geographically, High-income Asia Pacific and Central Asia exhibited the highest age-standardized YLD rates, while South and East Asia had the largest number of fractures and YLDs.</div></div><div><h3>Conclusions</h3><div>Our study provides an in-depth analysis of the fracture burden in Asia. From 1990 to 2021, the overall age-standardized fracture burden in Asia showed a gradual decline, yet the burden of hip fractures continued to increase. Asia holds the highest absolute number of fracture burden globally, with East Asia and South Asia being the primary regions contributing to this burden. The fracture burden increases with age in Asia, and women experience a higher fracture burden than men in older age groups. Strengthening surveillance and targeted prevention is essential to reduce the future fracture burden.</div></div><div><h3>The translational potential of this article</h3><div>Fracture is a kind of health problem with high incidence and serious disease burden in Asia. Although overall burden of disease for fractures in Asia from 1990 to 2021 was decreasing, the burden of hip fracture disease in Asia has con
{"title":"Epidemiology and disease burden of fractures in Asia, 1990–2021: An analysis for the Global Burden of Disease Study 2021","authors":"Yechao Shen , Boren Tan , Jiahao Zhang , Ning Zhang , Zhan Wang","doi":"10.1016/j.jot.2025.04.001","DOIUrl":"10.1016/j.jot.2025.04.001","url":null,"abstract":"<div><h3>Background</h3><div>Fractures are a significant global public health concern, imposing a substantial economic burden, particularly among the elderly. However, research on the fracture burden in Asia remains limited, highlighting the need for comprehensive and up-to-date studies to support the effective planning and allocation of healthcare resources across the region.</div></div><div><h3>Methods</h3><div>Using the Global Burden of Disease (GBD) 2021 database, we analyzed the age-standardized rates (ASRs) of incidence (ASIR), prevalence (ASPR), and years lived with disability (YLDs) (ASYR) associated with fracture burden across Asia. Our study explored trends over time, variations by age, sex, and country, and examined the correlation between fracture burden and the sociodemographic index (SDI).</div></div><div><h3>Results</h3><div>In 2021, fractures in Asia caused 91.3 million (95 % uncertainty interval, 83.65–99.47) incident cases, 232.71 million (95 % UI, (215.57–250.39) prevalent cases, and 12.97 million (95 % UI, 8.89–17.82) YLDs, with age-standardized rates of 1968.49 (95 % UI, 1799.15–2147.14) for incidence (ASIR), 4683.96 (95 % UI, 4347.58–5036.61) for prevalence (ASPR), and 261.72 (95 % UI, 179.43–358.94) for YLDs (ASYR) per 100,000 population. Despite a higher absolute burden, Asian age-standardized rates of fracture were slightly lower than the global average. For ASYR, the most burdensome fractures were those of the patella, tibia/fibula/ankle, hip, and pelvis. Between 1990 and 2021, fracture incident cases, prevalent cases, and YLDs in Asia increased markedly. Age and sex differences were observed, with the elderly experiencing the highest fracture burden, particularly for hip fractures in women. While men had a higher overall fracture burden, women faced a greater fracture disease burden in the elderly population. Geographically, High-income Asia Pacific and Central Asia exhibited the highest age-standardized YLD rates, while South and East Asia had the largest number of fractures and YLDs.</div></div><div><h3>Conclusions</h3><div>Our study provides an in-depth analysis of the fracture burden in Asia. From 1990 to 2021, the overall age-standardized fracture burden in Asia showed a gradual decline, yet the burden of hip fractures continued to increase. Asia holds the highest absolute number of fracture burden globally, with East Asia and South Asia being the primary regions contributing to this burden. The fracture burden increases with age in Asia, and women experience a higher fracture burden than men in older age groups. Strengthening surveillance and targeted prevention is essential to reduce the future fracture burden.</div></div><div><h3>The translational potential of this article</h3><div>Fracture is a kind of health problem with high incidence and serious disease burden in Asia. Although overall burden of disease for fractures in Asia from 1990 to 2021 was decreasing, the burden of hip fracture disease in Asia has con","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 281-290"},"PeriodicalIF":5.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882578","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 : 2025-04-29DOI: 10.1016/j.jot.2025.03.016
Cheng-Kung Cheng , Chengyan Lin , Yichao Luan
For Asia–Pacific countries used to long-term medical device manufacturing, developing innovative medical devices must be rooted in our profound research strength and mature medical productivity. Here, we developed a new model for achieving efficient translation through cooperation among local hospitals, universities, and industries and introduced the project manager system and Key Opinion Leader training. This “From SCI to FDA” model is a pivot for transferring cutting-edge research into valuable medical devices.
Translational potential of this article
This article presents a novel model for translating scientific research into innovative medical devices by fostering collaboration among hospitals, universities, and industries. By integrating clinical insights with academic expertise and industrial capabilities, this model addresses unmet clinical needs and bridges the gap between research and commercialization. Its potential lies in accelerating the translation of cutting-edge research into officially approved products, enhancing medical device innovation, and improving healthcare outcomes globally, particularly in Asia–Pacific countries.
{"title":"From “academic success” to “commercial success” —The model of medical device translation driven by SCI articles","authors":"Cheng-Kung Cheng , Chengyan Lin , Yichao Luan","doi":"10.1016/j.jot.2025.03.016","DOIUrl":"10.1016/j.jot.2025.03.016","url":null,"abstract":"<div><div>For Asia–Pacific countries used to long-term medical device manufacturing, developing innovative medical devices must be rooted in our profound research strength and mature medical productivity. Here, we developed a new model for achieving efficient translation through cooperation among local hospitals, universities, and industries and introduced the project manager system and Key Opinion Leader training. This “From SCI to FDA” model is a pivot for transferring cutting-edge research into valuable medical devices.</div></div><div><h3>Translational potential of this article</h3><div>This article presents a novel model for translating scientific research into innovative medical devices by fostering collaboration among hospitals, universities, and industries. By integrating clinical insights with academic expertise and industrial capabilities, this model addresses unmet clinical needs and bridges the gap between research and commercialization. Its potential lies in accelerating the translation of cutting-edge research into officially approved products, enhancing medical device innovation, and improving healthcare outcomes globally, particularly in Asia–Pacific countries.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 276-280"},"PeriodicalIF":5.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882577","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 : 2025-04-26DOI: 10.1016/j.jot.2025.03.021
Xingdong Xiang , Lei Huang , Wenchen Luo , Lieyang Qin , Mengxuan Bian , Weisin Chen , Guanjie Han , Ning Wang , Guokang Mo , Cheng Zhang , Yongxing Zhang , Huilin Yang , Shunyi Lu , Jian Zhang , Tengfei Fu
Background
Stroke-related sarcopenia can result in muscle mass loss and muscle fibers abnormality, significantly affecting muscle function. The clinical management of stroke-related sarcopenia still requires further research and investigation. This study aims to explore a promising therapy to restore muscle function and promote muscle regeneration in stroke-related sarcopenia, providing a new theory for stroke-related sarcopenia treatment.
Methods
Stroke-related sarcopenia rat model was established by using permanent middle cerebral artery occlusion (pMCAO) rat and treated with neuromuscular electrical stimulation (NMES). Electrical stimulation (ES) treatment in vitro was mimicked to test the effect of NMES on muscle regeneration in rat skeletal muscle satellite cells (MuSCs). Catwalk, H&E and Masson's trichrome staining, immunofluorescence, transcriptomic analysis, transmission electron microscopy, MuSCs transfection, autophagy flux detection, quantitative real-time PCR analysis, Co-Immunoprecipitation and Western Blot were used to investigate the role of NMES and its mechanism in stroke-related sarcopenia in vivo.
Results
After NMES treatment, muscle mass and myogenic differentiation were significantly increased in stroke-related sarcopenia rats. The NMES group had more stable gait, neater footprints, higher muscle wet weight, more voluminous morphology and more regenerated muscle fibers. Additionally, ES treatment induced myogenic differentiation in rat MuSCs in vitro. Transcriptomic analysis also showed that “AMPK signaling pathway” was enriched and genes upregulated in ES-treated cells, revealing ES treatment could activate the autophagy in an AMPK-ULK1-dependent mechanism in MuSCs. Besides, it was also founded that infusion of AMPK or ULK1 inhibitor, knockdown of AMPK or ULK1 in MuSCs could block the effect of myotube formation of ES.
Conclusion
NMES not only restores muscle function but also enhances myogenic activity and muscle regeneration via AMPK-ULK1 autophagy in stroke-related sarcopenia rats. Our study provides a promising strategy for the treatment of stroke-related sarcopenia.
The translational potential of this article
This study first demonstrates that NMES alleviates stroke-related sarcopenia by promoting MuSCs differentiation through AMPK-ULK1-autophagy axis. The findings reveal a novel therapeutic mechanism, suggesting that NMES can restore muscle function and enhance regeneration in stroke patients. By combining NMES with MuSCs-based therapies, this approach offers a promising strategy for clinical rehabilitation, potentially improving muscle mass and function in stroke survivors. The translational potential lies in its applicability to non-invasive, cost-effective treatments for sarcopenia, enhancing patients' quality of life.
{"title":"Neuromuscular electrical stimulation alleviates stroke-related sarcopenia by promoting satellite cells myogenic differentiation via AMPK-ULK1-Autophagy axis","authors":"Xingdong Xiang , Lei Huang , Wenchen Luo , Lieyang Qin , Mengxuan Bian , Weisin Chen , Guanjie Han , Ning Wang , Guokang Mo , Cheng Zhang , Yongxing Zhang , Huilin Yang , Shunyi Lu , Jian Zhang , Tengfei Fu","doi":"10.1016/j.jot.2025.03.021","DOIUrl":"10.1016/j.jot.2025.03.021","url":null,"abstract":"<div><h3>Background</h3><div>Stroke-related sarcopenia can result in muscle mass loss and muscle fibers abnormality, significantly affecting muscle function. The clinical management of stroke-related sarcopenia still requires further research and investigation. This study aims to explore a promising therapy to restore muscle function and promote muscle regeneration in stroke-related sarcopenia, providing a new theory for stroke-related sarcopenia treatment.</div></div><div><h3>Methods</h3><div>Stroke-related sarcopenia rat model was established by using permanent middle cerebral artery occlusion (pMCAO) rat and treated with neuromuscular electrical stimulation (NMES). Electrical stimulation (ES) treatment <em>in vitro</em> was mimicked to test the effect of NMES on muscle regeneration in rat skeletal muscle satellite cells (MuSCs). Catwalk, H&E and Masson's trichrome staining, immunofluorescence, transcriptomic analysis, transmission electron microscopy, MuSCs transfection, autophagy flux detection, quantitative real-time PCR analysis, Co-Immunoprecipitation and Western Blot were used to investigate the role of NMES and its mechanism in stroke-related sarcopenia <em>in vivo</em>.</div></div><div><h3>Results</h3><div>After NMES treatment, muscle mass and myogenic differentiation were significantly increased in stroke-related sarcopenia rats. The NMES group had more stable gait, neater footprints, higher muscle wet weight, more voluminous morphology and more regenerated muscle fibers. Additionally, ES treatment induced myogenic differentiation in rat MuSCs <em>in vitro</em>. Transcriptomic analysis also showed that “AMPK signaling pathway” was enriched and genes upregulated in ES-treated cells, revealing ES treatment could activate the autophagy in an AMPK-ULK1-dependent mechanism in MuSCs. Besides, it was also founded that infusion of AMPK or ULK1 inhibitor, knockdown of AMPK or ULK1 in MuSCs could block the effect of myotube formation of ES.</div></div><div><h3>Conclusion</h3><div>NMES not only restores muscle function but also enhances myogenic activity and muscle regeneration via AMPK-ULK1 autophagy in stroke-related sarcopenia rats. Our study provides a promising strategy for the treatment of stroke-related sarcopenia.</div></div><div><h3>The translational potential of this article</h3><div>This study first demonstrates that NMES alleviates stroke-related sarcopenia by promoting MuSCs differentiation through AMPK-ULK1-autophagy axis. The findings reveal a novel therapeutic mechanism, suggesting that NMES can restore muscle function and enhance regeneration in stroke patients. By combining NMES with MuSCs-based therapies, this approach offers a promising strategy for clinical rehabilitation, potentially improving muscle mass and function in stroke survivors. The translational potential lies in its applicability to non-invasive, cost-effective treatments for sarcopenia, enhancing patients' quality of life.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 249-264"},"PeriodicalIF":5.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877119","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}
Background/Objective: This study evaluated the impact of adipose tissue-derived mesenchymal stromal cells (ADSCs) on bone-tendon healing in rabbit anterior cruciate ligament (ACL) reconstruction.
Methods
Nineteen mature male Japanese White rabbits underwent bilateral ACL reconstruction. ADSC constructs were implanted in the right femoral bone tunnel of each rabbit (implant group), while the left knee served as the control group without implantation. Nine rabbits were sacrificed at 3 and 6 weeks post-surgery, while the remaining were sacrificed immediately post-surgery. Biomechanical and micro computed tomography evaluations were conducted on six rabbits, while histological observation was performed on the remaining three.
Results
showed: (1) The implant group exhibited a significantly greater failure load than the control group at 3 weeks post-surgery. (2) Initially, the amount of new bone in the femoral tunnel was lower in the implant group at 3 weeks but surpassed that of the control group by 6 weeks. (3) Histological analysis indicated faster bone-tendon healing in the implant group than that of the control.
Conclusion
These findings suggest a positive effect of ADSC constructs on bone-tendon healing post-ACL reconstruction in rabbits. However, further studies using larger animal models must confirm these effects comprehensively.
The translational potential of this article
The method of transplanting a scaffold-free autologous ADSC construct is a technique that can safely and reliably transplant ADSCs to the tendon-bone tunnel interface without using foreign substances. It can be applied to bone-tendon healing in ACL reconstruction surgery and other areas, such as the rotator cuff and Achilles tendon attachment site.
{"title":"Promotion of bone-tendon healing after ACL reconstruction using scaffold-free constructs comprising ADSCs produced by a bio-3D printer in rabbit models","authors":"Kotaro Higa , Daiki Murata , Chinatsu Azuma , Kotaro Nishida , Koichi Nakayama","doi":"10.1016/j.jot.2025.03.019","DOIUrl":"10.1016/j.jot.2025.03.019","url":null,"abstract":"<div><div>Background/Objective: This study evaluated the impact of adipose tissue-derived mesenchymal stromal cells (ADSCs) on bone-tendon healing in rabbit anterior cruciate ligament (ACL) reconstruction.</div></div><div><h3>Methods</h3><div>Nineteen mature male Japanese White rabbits underwent bilateral ACL reconstruction. ADSC constructs were implanted in the right femoral bone tunnel of each rabbit (implant group), while the left knee served as the control group without implantation. Nine rabbits were sacrificed at 3 and 6 weeks post-surgery, while the remaining were sacrificed immediately post-surgery. Biomechanical and micro computed tomography evaluations were conducted on six rabbits, while histological observation was performed on the remaining three.</div></div><div><h3>Results</h3><div>showed: (1) The implant group exhibited a significantly greater failure load than the control group at 3 weeks post-surgery. (2) Initially, the amount of new bone in the femoral tunnel was lower in the implant group at 3 weeks but surpassed that of the control group by 6 weeks. (3) Histological analysis indicated faster bone-tendon healing in the implant group than that of the control.</div></div><div><h3>Conclusion</h3><div>These findings suggest a positive effect of ADSC constructs on bone-tendon healing post-ACL reconstruction in rabbits. However, further studies using larger animal models must confirm these effects comprehensively.</div></div><div><h3>The translational potential of this article</h3><div>The method of transplanting a scaffold-free autologous ADSC construct is a technique that can safely and reliably transplant ADSCs to the tendon-bone tunnel interface without using foreign substances. It can be applied to bone-tendon healing in ACL reconstruction surgery and other areas, such as the rotator cuff and Achilles tendon attachment site.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 265-275"},"PeriodicalIF":5.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877168","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 : 2025-04-25DOI: 10.1016/j.jot.2025.04.005
Wenjie Hou , Xingru Shang , Xiaoxia Hao , Chunran Pan , Zehang Zheng , Yiwen Zhang , Xiaofeng Deng , Ruimin Chi , Jiawei Liu , Fengjing Guo , Kai Sun , Tao Xu
Background
Paraptosis is a novel form of programmed cell death, generally caused by disrupted proteostasis or alterations of redox homeostasis. However, its impact and underlying mechanisms on the pathology of osteoarthritis (OA) are still unclear. This study aimed to investigate the role and regulatory mechanism of SHP2 in chondrocyte paraptosis and the effects influenced by low-intensity pulsed ultrasound (LIPUS).
Methods
SHP2, a MAPK upstream intermediary, has been identified as one of the critical targets of IL-1β-induced paraptosis in the GEO and GeneCard databases. The expression of SHP2 in chondrocytes was regulated by either siRNA knockdown or plasmid overexpression. Additionally, adeno-associated viruses were injected into the knee joints of rats to explore whether SHP2 plays a role in the development of OA. The impact of LIPUS on paraptosis and OA was examined in IL-1β-induced chondrocytes and a post-traumatic OA model, with SHP2 regulation assessed at both cellular and animal levels.
Results
An increase in cellular reactive oxygen species (ROS) caused by IL-1β halts the growth of chondrocytes and induces paraptosis in the chondrocytes. IL-1β-induced paraptosis, manifested as endoplasmic reticulum (ER)-derived vacuolization, was mediated by ROS-mediated ER stress and MAPK activation. SHP2 facilitates ROS production, thereby exacerbating the chondrocytes paraptosis. SHP2 knockdown and ROS inhibition effectively reduced this process and significantly mitigated inflammation and cartilage degeneration. Furthermore, we discovered that LIPUS delayed OA progression by inhibiting the activation of the MAPK pathway, ER stress, and ER-derived vacuoles in chondrocytes, all of which play critical roles in paraptosis, through the downregulation of SHP2 expression. Results on animals showed that LIPUS inhibited cartilage degeneration and alleviated OA progression.
Conclusion
SHP2 exacerbates IL-1β-induced oxidative stress and the subsequent paraptosis in chondrocytes, promoting OA progression. LIPUS mitigates paraptosis by modulating SHP2, which in turn slows OA progression.
The translational potential of this article
This study indicates that a novel SHP2-mediated cell death mechanism, paraptosis, plays a role in post-traumatic OA progression. LIPUS helps maintain cartilage-subchondral bone unit integrity by targeting SHP2 inhibition. SHP2 emerges as a potential therapeutic target, while LIPUS provides a promising non-invasive approach for treating trauma-related OA.
背景自噬是一种新型的程序性细胞死亡，通常由蛋白稳态紊乱或氧化还原稳态改变引起。然而，其对骨关节炎（OA）病理的影响和内在机制仍不清楚。本研究旨在探讨SHP2在软骨细胞凋亡中的作用和调控机制以及低强度脉冲超声（LIPUS）对其的影响。方法SHP2是MAPK的上游中间体，在GEO和GeneCard数据库中已被确定为IL-1β诱导凋亡的关键靶点之一。SHP2在软骨细胞中的表达受siRNA敲除或质粒过表达调控。此外，还向大鼠膝关节中注射了腺相关病毒，以探讨SHP2是否在OA的发展过程中发挥作用。结果 IL-1β引起的细胞活性氧（ROS）增加会阻止软骨细胞的生长，并诱导软骨细胞发生凋亡。IL-1β诱导的凋亡表现为内质网（ER）产生的空泡化，是由ROS介导的ER应激和MAPK活化介导的。SHP2促进了ROS的产生，从而加剧了软骨细胞的aptosis。敲除 SHP2 和抑制 ROS 可有效减少这一过程，并显著减轻炎症和软骨退化。此外，我们还发现，LIPUS通过下调SHP2的表达，抑制了软骨细胞中MAPK通路的激活、ER应激和ER衍生空泡，从而延缓了OA的进展。动物实验结果表明，LIPUS 可抑制软骨变性，缓解 OA 进展。LIPUS通过调节SHP2减轻副aptosis，进而减缓OA的进展。本文的转化潜力这项研究表明，SHP2介导的一种新型细胞死亡机制--副aptosis在创伤后OA进展中发挥了作用。LIPUS通过靶向抑制SHP2有助于维持软骨-软骨下骨单元的完整性。SHP2 成为潜在的治疗靶点，而 LIPUS 则为治疗创伤相关的 OA 提供了一种前景广阔的非侵入性方法。
{"title":"SHP2-mediated ROS activation induces chondrocyte paraptosis in osteoarthritis and is attenuated by low-intensity pulsed ultrasound","authors":"Wenjie Hou , Xingru Shang , Xiaoxia Hao , Chunran Pan , Zehang Zheng , Yiwen Zhang , Xiaofeng Deng , Ruimin Chi , Jiawei Liu , Fengjing Guo , Kai Sun , Tao Xu","doi":"10.1016/j.jot.2025.04.005","DOIUrl":"10.1016/j.jot.2025.04.005","url":null,"abstract":"<div><h3>Background</h3><div>Paraptosis is a novel form of programmed cell death, generally caused by disrupted proteostasis or alterations of redox homeostasis. However, its impact and underlying mechanisms on the pathology of osteoarthritis (OA) are still unclear. This study aimed to investigate the role and regulatory mechanism of SHP2 in chondrocyte paraptosis and the effects influenced by low-intensity pulsed ultrasound (LIPUS).</div></div><div><h3>Methods</h3><div>SHP2, a MAPK upstream intermediary, has been identified as one of the critical targets of IL-1β-induced paraptosis in the GEO and GeneCard databases. The expression of SHP2 in chondrocytes was regulated by either siRNA knockdown or plasmid overexpression. Additionally, adeno-associated viruses were injected into the knee joints of rats to explore whether SHP2 plays a role in the development of OA. The impact of LIPUS on paraptosis and OA was examined in IL-1β-induced chondrocytes and a post-traumatic OA model, with SHP2 regulation assessed at both cellular and animal levels.</div></div><div><h3>Results</h3><div>An increase in cellular reactive oxygen species (ROS) caused by IL-1β halts the growth of chondrocytes and induces paraptosis in the chondrocytes. IL-1β-induced paraptosis, manifested as endoplasmic reticulum (ER)-derived vacuolization, was mediated by ROS-mediated ER stress and MAPK activation. SHP2 facilitates ROS production, thereby exacerbating the chondrocytes paraptosis. SHP2 knockdown and ROS inhibition effectively reduced this process and significantly mitigated inflammation and cartilage degeneration. Furthermore, we discovered that LIPUS delayed OA progression by inhibiting the activation of the MAPK pathway, ER stress, and ER-derived vacuoles in chondrocytes, all of which play critical roles in paraptosis, through the downregulation of SHP2 expression. Results on animals showed that LIPUS inhibited cartilage degeneration and alleviated OA progression.</div></div><div><h3>Conclusion</h3><div>SHP2 exacerbates IL-1β-induced oxidative stress and the subsequent paraptosis in chondrocytes, promoting OA progression. LIPUS mitigates paraptosis by modulating SHP2, which in turn slows OA progression.</div></div><div><h3>The translational potential of this article</h3><div>This study indicates that a novel SHP2-mediated cell death mechanism, paraptosis, plays a role in post-traumatic OA progression. LIPUS helps maintain cartilage-subchondral bone unit integrity by targeting SHP2 inhibition. SHP2 emerges as a potential therapeutic target, while LIPUS provides a promising non-invasive approach for treating trauma-related OA.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 233-248"},"PeriodicalIF":5.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873722","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 : 2025-04-25DOI: 10.1016/j.jot.2025.04.008
Chao Jiang , Yuhang Gong , Xinyu Wu , Jiangjie Chen , Yiyu Chen , Jingyao Chen , Fang Tang , Zhiyu Fang , Yuxuan Bao , Jiajing Ye , Zhangfu Wang , Zhenghua Hong
Background
Osteoarthritis (OA), the most prevalent form of arthritis, is swiftly emerging as a chronic health condition, that poses the primary cause of disability and significant socioeconomic burden. Despite its prevalence, effective therapeutic options for OA remain elusive. This study seeks to explore the therapeutic potential of edaravone (EDA), a FDA-approved free radical scavenger, in the context of OA development and to elucidate its underlying mechanisms.
Methods
In vitro, oxidative stress models were induced by stimulating chondrocytes with t-butylhydroperoxide (TBHP); then, we investigated the influence of EDA on chondrocyte dysfunction, apoptosis, inflammatory responses and mitochondrial function in TBHP-treated chondrocytes, along with the underlying mechanisms. In vivo, destabilization of the medial meniscus (DMM) model was used to investigate the impact of EDA on OA progression. Nrf2−/− mice were applied to determine the potential role of NRF2 as a target for EDA.
Results
EDA notably alleviates chondrocyte dysfunction triggered by oxidative stress, safeguards chondrocytes from apoptosis and inflammatory responses, and preserves mitochondrial function and redox balance within chondrocytes. At the molecular level, EDA appears to halt the progression of OA by engaging and activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which is crucial for maintaining mitochondrial function and redox equilibrium. Notably, the protective effects of EDA on OA are abolished in Nrf2−/− mice, underscoring the significance of the NRF2 signaling pathway in mediating EDA's therapeutic effects.
Conclusion
EDA has the potential to mitigate chondrocyte degeneration, thereby slowing the progression of OA. Thus, EDA may represent a novel therapeutic agent for the treatment of OA, potentially expanding its clinical utility.
The translational potential of this article
As a clinically licensed drug used for the treatment of neurological disorders, edaravone has shown promising therapeutic effects on OA development. Mechanistically, edaravone stabilized mitochondrial function and maintained redox homeostasis by activating NRF2 signaling pathway. The protective effects of edaravone against OA were verified in vivo and in vitro. These findings presented robust evidence for repurposing edaravone for the treatment of OA in clinic.
{"title":"Therapeutic effect of edaravone on osteoarthritis: targeting NRF2 signaling and mitochondrial function","authors":"Chao Jiang , Yuhang Gong , Xinyu Wu , Jiangjie Chen , Yiyu Chen , Jingyao Chen , Fang Tang , Zhiyu Fang , Yuxuan Bao , Jiajing Ye , Zhangfu Wang , Zhenghua Hong","doi":"10.1016/j.jot.2025.04.008","DOIUrl":"10.1016/j.jot.2025.04.008","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA), the most prevalent form of arthritis, is swiftly emerging as a chronic health condition, that poses the primary cause of disability and significant socioeconomic burden. Despite its prevalence, effective therapeutic options for OA remain elusive. This study seeks to explore the therapeutic potential of edaravone (EDA), a FDA-approved free radical scavenger, in the context of OA development and to elucidate its underlying mechanisms.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, oxidative stress models were induced by stimulating chondrocytes with t-butylhydroperoxide (TBHP); then, we investigated the influence of EDA on chondrocyte dysfunction, apoptosis, inflammatory responses and mitochondrial function in TBHP-treated chondrocytes, along with the underlying mechanisms. <em>In vivo</em>, destabilization of the medial meniscus (DMM) model was used to investigate the impact of EDA on OA progression. <em>Nrf2</em><sup>−/−</sup> mice were applied to determine the potential role of NRF2 as a target for EDA.</div></div><div><h3>Results</h3><div>EDA notably alleviates chondrocyte dysfunction triggered by oxidative stress, safeguards chondrocytes from apoptosis and inflammatory responses, and preserves mitochondrial function and redox balance within chondrocytes. At the molecular level, EDA appears to halt the progression of OA by engaging and activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which is crucial for maintaining mitochondrial function and redox equilibrium. Notably, the protective effects of EDA on OA are abolished in <em>Nrf2</em><sup>−/−</sup> mice, underscoring the significance of the NRF2 signaling pathway in mediating EDA's therapeutic effects.</div></div><div><h3>Conclusion</h3><div>EDA has the potential to mitigate chondrocyte degeneration, thereby slowing the progression of OA. Thus, EDA may represent a novel therapeutic agent for the treatment of OA, potentially expanding its clinical utility.</div></div><div><h3>The translational potential of this article</h3><div>As a clinically licensed drug used for the treatment of neurological disorders, edaravone has shown promising therapeutic effects on OA development. Mechanistically, edaravone stabilized mitochondrial function and maintained redox homeostasis by activating NRF2 signaling pathway. The protective effects of edaravone against OA were verified <em>in vivo</em> and <em>in vitro</em>. These findings presented robust evidence for repurposing edaravone for the treatment of OA in clinic.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 220-232"},"PeriodicalIF":5.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869086","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 : 2025-04-24DOI: 10.1016/j.jot.2025.03.022
Zhuang Miao , Songlin Li , Yange Luo , Shihao Li , Ziyue Chu , Weibo Zheng , Xuezhou Li , Qunshan Lu , Peilai Liu
Background
High body-mass-index (BMI) has been shown to be a risk factor for knee osteoarthritis (KOA). Previous studies have examined the global or regional burden of osteoarthritis in multiple joints, including the hip, knee, and hand. However, there is no comprehensive analysis and prediction of the global burden of KOA attributed to high BMI.
Methods
Disease burden of KOA attributable to high BMI, from 1990 to 2021, were extracted from the Global Burden of Disease (GBD) 2021. Trends were analyzed at the global, regional, and national levels, with subgroup analyses. Joinpoint regression, age-period-cohort model, decomposition analysis, cross-country inequalities were used to analyze the trend of disease burden from multiple dimensions. Autoregressive integrated moving average (ARIMA) model, a time-series based forecasting algorithms, was applied to predict the burden for the next 20 years.
Results
From 1990 to 2021, the risk factor attribution of high BMI in KOA increased from 25.44 % (95 % CI: −2.38 %–48.66 %) to 33.52 % (95 % CI: −3.38 %–61.92 %). Globally, regionally, and nationally, the burden of KOA attributed to high BMI showed a sharp increase. Except for the decline observed in high sociodemographic index (SDI) regions from 2000 to 2005, the burden exhibited an upward trend across all other time periods and regions. Age, cohort, and period had significant impacts on disease burden. Both population growth and epidemiological changes contributed positively to the increase in the burden. Economic and social development led to increasing disparities, with lower-SDI countries showing better health outcomes. ARIMA model showed that a continued rise in the burden of KOA due to high BMI globally through 2041.
Conclusions
KOA attributable to high BMI has imposed a substantial burden globally, regionally, and nationally over the past 30 years, with a marked increase. The projections indicate a further increase in the global burden over the next 20 years. Measures need to be taken for targeted preventive intervention.
The translational potential of this article
High BMI is an important risk factor for KOA. The disease burden of KOA attributable to high BMI has increased significantly over the past 30 years. This burden is concentrated in economically developed areas, although the growth rate in less developed regions surpasses that of developed regions. This study suggested that targeted interventions addressing disease patterns across socioeconomic contexts are crucial to mitigating the burden of KOA attributable to high BMI. In addition, it is necessary to pay more attention to the disease burden of female.
{"title":"Trends, inequalities and time-series based prediction of knee osteoarthritis attributed to high body-mass-index: findings from global burden of disease 2021","authors":"Zhuang Miao , Songlin Li , Yange Luo , Shihao Li , Ziyue Chu , Weibo Zheng , Xuezhou Li , Qunshan Lu , Peilai Liu","doi":"10.1016/j.jot.2025.03.022","DOIUrl":"10.1016/j.jot.2025.03.022","url":null,"abstract":"<div><h3>Background</h3><div>High body-mass-index (BMI) has been shown to be a risk factor for knee osteoarthritis (KOA). Previous studies have examined the global or regional burden of osteoarthritis in multiple joints, including the hip, knee, and hand. However, there is no comprehensive analysis and prediction of the global burden of KOA attributed to high BMI.</div></div><div><h3>Methods</h3><div>Disease burden of KOA attributable to high BMI, from 1990 to 2021, were extracted from the Global Burden of Disease (GBD) 2021. Trends were analyzed at the global, regional, and national levels, with subgroup analyses. Joinpoint regression, age-period-cohort model, decomposition analysis, cross-country inequalities were used to analyze the trend of disease burden from multiple dimensions. Autoregressive integrated moving average (ARIMA) model, a time-series based forecasting algorithms, was applied to predict the burden for the next 20 years.</div></div><div><h3>Results</h3><div>From 1990 to 2021, the risk factor attribution of high BMI in KOA increased from 25.44 % (95 % CI: −2.38 %–48.66 %) to 33.52 % (95 % CI: −3.38 %–61.92 %). Globally, regionally, and nationally, the burden of KOA attributed to high BMI showed a sharp increase. Except for the decline observed in high sociodemographic index (SDI) regions from 2000 to 2005, the burden exhibited an upward trend across all other time periods and regions. Age, cohort, and period had significant impacts on disease burden. Both population growth and epidemiological changes contributed positively to the increase in the burden. Economic and social development led to increasing disparities, with lower-SDI countries showing better health outcomes. ARIMA model showed that a continued rise in the burden of KOA due to high BMI globally through 2041.</div></div><div><h3>Conclusions</h3><div>KOA attributable to high BMI has imposed a substantial burden globally, regionally, and nationally over the past 30 years, with a marked increase. The projections indicate a further increase in the global burden over the next 20 years. Measures need to be taken for targeted preventive intervention.</div></div><div><h3>The translational potential of this article</h3><div>High BMI is an important risk factor for KOA. The disease burden of KOA attributable to high BMI has increased significantly over the past 30 years. This burden is concentrated in economically developed areas, although the growth rate in less developed regions surpasses that of developed regions. This study suggested that targeted interventions addressing disease patterns across socioeconomic contexts are crucial to mitigating the burden of KOA attributable to high BMI. In addition, it is necessary to pay more attention to the disease burden of female.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 209-219"},"PeriodicalIF":5.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869088","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 : 2025-04-24DOI: 10.1016/j.jot.2025.04.006
Qinghe Zeng , Yongjia Feng , Haipeng Huang , Kaiao Zou , Wenzhe Chen , Xuefeng Li , Yuliang Huang , Weidong Wang , Wenhua Yuan , Pinger Wang , Peijian Tong , Hongting Jin , Jiali Chen
Background
Joint bleeding (hemarthrosis) is a major manifestation of joint trauma, especially repeated and spontaneous in hemophilia patients. Hemarthrosis has been identified to induce the excessive reactive oxygen species (ROS) accumulation and permanent damage in articular cartilage. Dihydroartemisinin (DHA), a well-known clinical anti-malaria drug with few sides effects therapy, has been reported to possess anti-oxidative activity. This study was aimed at exploring the effect of DHA on blood-induced cartilage erosion and its underlying mechanisms.
Methods
Two distinct hemarthrosis models were constructed respectively by fresh blood joint injection in WT and joint needle puncture in F8−/− mice, and then treated with DHA (10 or 20 mg/kg/day) for 4 weeks. In vitro chondrocytes treated with frozen-thaw blood and DHA (1, 5 or 10 μM) for 24 h. Histopathological, immunofluorescence and western blotting were investigated to demonstrate the effects of DHA on blood-induced chondrocyte senescence, ROS accumulation and extracellular matrix (ECM) degradation. Additionally, Nrf2 inhibitor (MLB385, 30 mg/kg for once a four days) and Nrf2-siRNA were used to investigate the relationship between DHA and Nrf2/Keap1 signaling in vitro and in vivo, respectively.
Results
DHA remarkably ameliorated the cartilage degeneration in both two hemarthrosis models. Similarly, in vitro experiments confirmed that DHA promoted the synthesis of ECM in blood-stimulated chondrocytes with a dose-dependent manner. DHA also effectively suppressed blood-induced chondrocyte senescence and ROS accumulation. Mechanistically, DHA activated the Nrf2 signaling by accelerating Keap1 ubiquitination and degradation. Furthermore, Nrf2 siRNA and antagonist abolished the anti-senescence and anti-oxidative functions of DHA, resulting the severe cartilage degeneration in bleeding joint of F8−/− mice.
Conclusion
Our findings indicate that DHA effectively reduces chondrocyte senescence and mitigates cartilage destruction following hemarthrosis via activation of Nrf2/Keap1 signaling pathway.
The Translational potential of this article
On the one hand, this study highlights the important role of chondrocyte senescence in hemarthrosis-induced cartilage degradation, implying that inhibiting chondrocyte senescence may be a viable therapeutic strategy for blood-induced arthropathy. On the other hand, our findings demonstrate the remarkable chondroprotective effect of DHA in bleeding joint by modulating the Nrf2/Keap1 anti-oxidative signaling pathway, suggesting DHA may serve as a potential candidate drug for the therapy of blood-induced arthropathy.
{"title":"Dihydroartemisinin ameliorates hemarthrosis-induced cartilage degeneration by suppressing chondrocyte senescence via activation of Keap1-Nrf2 signaling pathway","authors":"Qinghe Zeng , Yongjia Feng , Haipeng Huang , Kaiao Zou , Wenzhe Chen , Xuefeng Li , Yuliang Huang , Weidong Wang , Wenhua Yuan , Pinger Wang , Peijian Tong , Hongting Jin , Jiali Chen","doi":"10.1016/j.jot.2025.04.006","DOIUrl":"10.1016/j.jot.2025.04.006","url":null,"abstract":"<div><h3>Background</h3><div>Joint bleeding (hemarthrosis) is a major manifestation of joint trauma, especially repeated and spontaneous in hemophilia patients. Hemarthrosis has been identified to induce the excessive reactive oxygen species (ROS) accumulation and permanent damage in articular cartilage. Dihydroartemisinin (DHA), a well-known clinical anti-malaria drug with few sides effects therapy, has been reported to possess anti-oxidative activity. This study was aimed at exploring the effect of DHA on blood-induced cartilage erosion and its underlying mechanisms.</div></div><div><h3>Methods</h3><div>Two distinct hemarthrosis models were constructed respectively by fresh blood joint injection in WT and joint needle puncture in <em>F8</em><sup><em>−/−</em></sup> mice, and then treated with DHA (10 or 20 mg/kg/day) for 4 weeks. <em>In vitro</em> chondrocytes treated with frozen-thaw blood and DHA (1, 5 or 10 μM) for 24 h. Histopathological, immunofluorescence and western blotting were investigated to demonstrate the effects of DHA on blood-induced chondrocyte senescence, ROS accumulation and extracellular matrix (ECM) degradation. Additionally, Nrf2 inhibitor (MLB385, 30 mg/kg for once a four days) and Nrf2-siRNA were used to investigate the relationship between DHA and Nrf2/Keap1 signaling <em>in vitro</em> and <em>in vivo</em>, respectively.</div></div><div><h3>Results</h3><div>DHA remarkably ameliorated the cartilage degeneration in both two hemarthrosis models. Similarly, <em>in vitro</em> experiments confirmed that DHA promoted the synthesis of ECM in blood-stimulated chondrocytes with a dose-dependent manner. DHA also effectively suppressed blood-induced chondrocyte senescence and ROS accumulation. Mechanistically, DHA activated the Nrf2 signaling by accelerating Keap1 ubiquitination and degradation. Furthermore, Nrf2 siRNA and antagonist abolished the anti-senescence and anti-oxidative functions of DHA, resulting the severe cartilage degeneration in bleeding joint of <em>F8</em><sup><em>−/−</em></sup> mice.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that DHA effectively reduces chondrocyte senescence and mitigates cartilage destruction following hemarthrosis via activation of Nrf2/Keap1 signaling pathway.</div></div><div><h3>The Translational potential of this article</h3><div>On the one hand, this study highlights the important role of chondrocyte senescence in hemarthrosis-induced cartilage degradation, implying that inhibiting chondrocyte senescence may be a viable therapeutic strategy for blood-induced arthropathy. On the other hand, our findings demonstrate the remarkable chondroprotective effect of DHA in bleeding joint by modulating the Nrf2/Keap1 anti-oxidative signaling pathway, suggesting DHA may serve as a potential candidate drug for the therapy of blood-induced arthropathy.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 192-208"},"PeriodicalIF":5.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869087","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 : 2025-04-23DOI: 10.1016/j.jot.2025.04.007
Jing Zhang , Wenhui Hu , Yuheng Li , Fei Kang , Xuan Yao , Jianmei Li , Shiwu Dong
<div><h3>Background</h3><div>Osteoarthritis (OA) is a chronic joint disorder that predominantly affects middle-aged or elderly individuals. Subchondral bone remodeling due to osteoclast hyperactivation is regarded as a major feature of early OA. During osteoclast fusion and multinucleation, the cytoskeleton reorganization leads to the formation of actin belts and ultimately bone resorption. Membrane-associated guanylate kinase with an inverted repeat member 1 (MAGI1) is a scaffolding protein that is crucial for linking the extracellular environment to intracellular signaling pathways and cytoskeleton. However, the role of MAGI1 in subchondral bone osteoclast fusion remains unclear.</div></div><div><h3>Methods</h3><div>In this study, we collected knee joint samples from OA patients and established the OA mouse model to examine the expression of MAGI1. Furthermore, we established the OA rat model and locally injected rAAV9-mediated shMagi1 into the subchondral bone to knock down MAGI1 expression. Micro-CT, histological staining, and immunofluorescence were employed to assess the effects of MAGI1 knockdown on subchondral bone homeostasis and OA process. We isolated and cultured osteoclasts from femoral and tibial bone marrow. Receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclasts served as an <em>in vitro</em> model for OA and underwent RNA sequencing. We employed gain- and loss-of-function experiments using MAGI1-overexpression plasmids and small interfering RNA to explore the role of MAGI1 in osteoclast differentiation. Further molecular experiments, including RT-qPCR, western blotting, immunofluorescence staining, and LC-MS/MS were performed to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>MAGI1 expression was significantly downregulated during RANKL-induced osteoclastogenesis <em>in vitro</em>. Additionally, a progressive decrease in MAGI1 expression was consistently observed in both knee joint samples from OA patients and mouse OA models, correlating with OA progression. Knockdown of MAGI1 in subchondral bone increased osteoclast numbers and worsened subchondral bone microarchitecture and cartilage degeneration; MAGI1 knockdown rats exhibited elevated PDGF-BB, Netrin-1, and CGRP<sup>+</sup> sensory innervation. Overexpression and knockdown of MAGI1 suppressed and promoted osteoclast differentiation, respectively. Mechanistically, MAGI1 overexpression decreased the levels of RhoA, ROCK1, and p-p65 in RANKL-treated osteoclasts, which was rescued by the addition of RhoA activator narciclasine.</div></div><div><h3>Conclusion</h3><div>Our results demonstrate that MAGI1 suppresses osteoclast fusion through the RhoA/ROCK1 signaling pathway, targeting MAGI1 in subchondral bone osteoclasts may be a promising therapeutic strategy mitigate the advancement of OA.</div></div><div><h3>The translational potential of this article</h3><div>This study reveals that the scaffold protein MAGI1 participates in osteoar
{"title":"MAGI1 attenuates osteoarthritis by regulating osteoclast fusion in subchondral bone through the RhoA-ROCK1 signaling pathway","authors":"Jing Zhang , Wenhui Hu , Yuheng Li , Fei Kang , Xuan Yao , Jianmei Li , Shiwu Dong","doi":"10.1016/j.jot.2025.04.007","DOIUrl":"10.1016/j.jot.2025.04.007","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a chronic joint disorder that predominantly affects middle-aged or elderly individuals. Subchondral bone remodeling due to osteoclast hyperactivation is regarded as a major feature of early OA. During osteoclast fusion and multinucleation, the cytoskeleton reorganization leads to the formation of actin belts and ultimately bone resorption. Membrane-associated guanylate kinase with an inverted repeat member 1 (MAGI1) is a scaffolding protein that is crucial for linking the extracellular environment to intracellular signaling pathways and cytoskeleton. However, the role of MAGI1 in subchondral bone osteoclast fusion remains unclear.</div></div><div><h3>Methods</h3><div>In this study, we collected knee joint samples from OA patients and established the OA mouse model to examine the expression of MAGI1. Furthermore, we established the OA rat model and locally injected rAAV9-mediated shMagi1 into the subchondral bone to knock down MAGI1 expression. Micro-CT, histological staining, and immunofluorescence were employed to assess the effects of MAGI1 knockdown on subchondral bone homeostasis and OA process. We isolated and cultured osteoclasts from femoral and tibial bone marrow. Receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclasts served as an <em>in vitro</em> model for OA and underwent RNA sequencing. We employed gain- and loss-of-function experiments using MAGI1-overexpression plasmids and small interfering RNA to explore the role of MAGI1 in osteoclast differentiation. Further molecular experiments, including RT-qPCR, western blotting, immunofluorescence staining, and LC-MS/MS were performed to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>MAGI1 expression was significantly downregulated during RANKL-induced osteoclastogenesis <em>in vitro</em>. Additionally, a progressive decrease in MAGI1 expression was consistently observed in both knee joint samples from OA patients and mouse OA models, correlating with OA progression. Knockdown of MAGI1 in subchondral bone increased osteoclast numbers and worsened subchondral bone microarchitecture and cartilage degeneration; MAGI1 knockdown rats exhibited elevated PDGF-BB, Netrin-1, and CGRP<sup>+</sup> sensory innervation. Overexpression and knockdown of MAGI1 suppressed and promoted osteoclast differentiation, respectively. Mechanistically, MAGI1 overexpression decreased the levels of RhoA, ROCK1, and p-p65 in RANKL-treated osteoclasts, which was rescued by the addition of RhoA activator narciclasine.</div></div><div><h3>Conclusion</h3><div>Our results demonstrate that MAGI1 suppresses osteoclast fusion through the RhoA/ROCK1 signaling pathway, targeting MAGI1 in subchondral bone osteoclasts may be a promising therapeutic strategy mitigate the advancement of OA.</div></div><div><h3>The translational potential of this article</h3><div>This study reveals that the scaffold protein MAGI1 participates in osteoar","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 167-181"},"PeriodicalIF":5.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858925","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 : 2025-04-23DOI: 10.1016/j.jot.2025.04.004
Simon von Kroge , Constantin Schmidt , Sebastian Butscheidt , Malte Ohlmeier , Michael Amling , Frank Timo Beil , Thorsten Gehrke , Klaus Püschel , Michael Hahn , Tim Rolvien
Background
Periprosthetic bone loss is a common clinical problem in hip arthroplasty that must be addressed during revision surgery to achieve adequate implant stability. Although bone allografts represent the clinical standard among substitute materials used, evidence of their regenerative potential at the microstructural, cellular, and compositional level is lacking.
Methods
A multiscale imaging approach comprising contact radiography, undecalcified histology, scanning electron microscopy, and nanoindentation was employed on human femoral explants obtained postmortem many years after allograft use during revision surgery.
Results
The degree of skeletal regeneration through allograft incorporation between host bone and allograft bone was highly dependent on the defect depth (R2 = 0.94, p < 0.001), while no association between the allograft time in situ and incorporation (R2 = 0.06, p = 0.61) was apparent. The host bone-allograft interface showed a high overlap of 4.0 ± 2.9 mm and was characterized by active bone remodelling, as indicated by osteoid accumulation, high abundance of bone cells and vasculature. While bone cement generally limited the incorporation process, the osteocytic canalicular system of the host bone reached the allograft interface to guide bone remodelling.
Conclusion
This is the first multiscale, histomorphometry-based evaluation of bone allografts used in revision hip arthroplasty for femoral bone loss in humans, demonstrating that they adequately facilitate skeletal regeneration through osteoconduction and subsequent remodelling.
The translational potential of this article
This study identified the mechanisms and determinants of femoral defect regeneration through allografts on the basis of a unique sample collection. While our results support their favourable clinical outcomes, the scientific basis for incomplete incorporation is also demonstrated.
背景：假体周围骨丢失是髋关节置换术中常见的临床问题，必须在翻修手术中加以解决，以获得足够的假体稳定性。尽管同种异体骨移植物代表了临床使用的替代材料的标准，但在微观结构，细胞和成分水平上缺乏其再生潜力的证据。方法采用多尺度成像方法，包括接触x线摄影、未钙化组织学、扫描电镜和纳米压痕，对翻修手术中使用同种异体移植多年后获得的人股骨外植体进行扫描。结果同种异体骨与宿主骨结合的骨再生程度与骨缺损深度高度相关(R2 = 0.94, p <；0.001)，而同种异体移植物原位时间与植入无明显相关性（R2 = 0.06, p = 0.61）。宿主骨-同种异体移植物界面高度重叠（4.0±2.9 mm），具有骨重构活跃的特征，表现为类骨积累、骨细胞和血管的高丰度。骨水泥通常限制了骨融合过程，宿主骨的骨细胞小管系统到达同种异体移植物界面，引导骨重建。这是第一个基于组织形态学的多尺度评估异体骨移植物用于人类股骨骨丢失的翻修髋关节置换术，证明它们通过骨传导和随后的重塑充分促进骨骼再生。本研究通过独特的样本收集确定了同种异体移植股骨缺损再生的机制和决定因素。虽然我们的结果支持其良好的临床结果，但也证明了不完全结合的科学依据。
{"title":"Allografts promote skeletal regeneration of periprosthetic femoral bone loss","authors":"Simon von Kroge , Constantin Schmidt , Sebastian Butscheidt , Malte Ohlmeier , Michael Amling , Frank Timo Beil , Thorsten Gehrke , Klaus Püschel , Michael Hahn , Tim Rolvien","doi":"10.1016/j.jot.2025.04.004","DOIUrl":"10.1016/j.jot.2025.04.004","url":null,"abstract":"<div><h3>Background</h3><div>Periprosthetic bone loss is a common clinical problem in hip arthroplasty that must be addressed during revision surgery to achieve adequate implant stability. Although bone allografts represent the clinical standard among substitute materials used, evidence of their regenerative potential at the microstructural, cellular, and compositional level is lacking.</div></div><div><h3>Methods</h3><div>A multiscale imaging approach comprising contact radiography, undecalcified histology, scanning electron microscopy, and nanoindentation was employed on human femoral explants obtained postmortem many years after allograft use during revision surgery.</div></div><div><h3>Results</h3><div>The degree of skeletal regeneration through allograft incorporation between host bone and allograft bone was highly dependent on the defect depth (R<sup>2</sup> = 0.94, <em>p <</em> 0.001), while no association between the allograft time <em>in situ</em> and incorporation (R<sup>2</sup> = 0.06, <em>p</em> = 0.61) was apparent. The host bone-allograft interface showed a high overlap of 4.0 ± 2.9 mm and was characterized by active bone remodelling, as indicated by osteoid accumulation, high abundance of bone cells and vasculature. While bone cement generally limited the incorporation process, the osteocytic canalicular system of the host bone reached the allograft interface to guide bone remodelling.</div></div><div><h3>Conclusion</h3><div>This is the first multiscale, histomorphometry-based evaluation of bone allografts used in revision hip arthroplasty for femoral bone loss in humans, demonstrating that they adequately facilitate skeletal regeneration through osteoconduction and subsequent remodelling.</div></div><div><h3>The translational potential of this article</h3><div>This study identified the mechanisms and determinants of femoral defect regeneration through allografts on the basis of a unique sample collection. While our results support their favourable clinical outcomes, the scientific basis for incomplete incorporation is also demonstrated.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 182-191"},"PeriodicalIF":5.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858926","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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