Journal of Orthopaedic Translation最新文献

{"title":"Fibrocartilage hyalinization: A potential therapeutic strategy for articular fibrocartilage","authors":"Jiawei Li ,&nbsp;Huiming Jiang ,&nbsp;Guihua Tan ,&nbsp;Zhongyang Lv ,&nbsp;Zizheng Liu ,&nbsp;Hu Guo ,&nbsp;Ziying Sun ,&nbsp;Xingquan Xu ,&nbsp;Dongquan Shi","doi":"10.1016/j.jot.2025.04.013","DOIUrl":"10.1016/j.jot.2025.04.013","url":null,"abstract":"<div><div>Articular fibrocartilage is commonly observed on the joint surface in osteoarthritis (OA) or cartilage injury, often seen as a result of cartilage degeneration. Compared to hyaline cartilage, fibrocartilage exhibits inferior mechanical properties and biological functions, which contribute to further cartilage degeneration and the progression of OA. Despite this, research on cartilage regeneration has not sufficiently addressed the specific challenges and strategies related to fibrocartilage. Although fibrocartilage formation is an unavoidable outcome during cartilage repair, it offers several benefits in the regeneration process, such as providing a natural cell source and establishing a strong integration with surrounding tissues. Recently, a therapeutic approach focused on the <em>in-situ</em> modification of fibrocartilage to promote hyaline cartilage regeneration, referred to as “fibrocartilage hyalinization”, has been proposed. Our recent work has demonstrated the feasibility of converting existing fibrocartilage into hyaline cartilage <em>in vivo</em> within the injured area. Key elements of this strategy include modifying the extracellular matrix (ECM), targeting fibrotic chondrocytes, and altering the local microenvironment. This review summarizes the current understanding of articular fibrocartilage's characteristics and mechanisms, while also discussing potential approaches and the feasibility of fibrocartilage hyalinization for cartilage regeneration.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 313-324"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent variation in bone adaptation: from degeneration to regeneration","authors":"Song Chen ,&nbsp;Jhanvee Patel ,&nbsp;Torey Katzmeyer ,&nbsp;Ming Pei","doi":"10.1016/j.jot.2025.04.011","DOIUrl":"10.1016/j.jot.2025.04.011","url":null,"abstract":"<div><div>While known sex differences in bone health exist, scientific studies on bone degeneration and regeneration frequently disregard sex impact as a variable in outcomes. Evidence has established a higher risk of osteoporosis and increased bone degradation rates in women when compared to men. Accumulating research suggests that this disparity is also present in bone regeneration and repair. However, no comprehensive review highlighting the influence of sex currently exists in this field. This paper aims to review the information presently available on the cellular mechanisms behind skeletal sexual dimorphism specific to hormones and bone's degenerative and regenerative sex differences. This review will discuss the optimization of personalized regenerative therapies accounting for sex. The review emphasizes that sex impact must further be investigated to advance the field of bone regeneration and improve patient outcomes and quality of life.</div><div>As translational medicine is JOT's focus, authors must highlight the translational potential or clinical significance of their work in both the abstract and the discussion. To this effect, it is required to include a statement following the abstract (included in the abstract word count) under the following heading: \"The Translational Potential of this Article\". 2. Please re-edit the reference list according to the following guidelines: 1) The last names and initials of all the authors up to 6 should be included, but when authors number 7 or more, list the first 6 authors only followed by 'et al'; 2) The \"[eng]\" in the reference list should be removed (if any); 3) Reference to a standard journal article (Please pay particular attention to the formatting, word capitalization, spacing and style): “Niemansburg SL, van Delden JJ, Dhert WJ, Bredenoord AL. Regenerative medicine interventions for orthopedic disorders: ethical issues in the translation into patients. Regen Med 2013;8:65–73.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 325-343"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solute transport from synovial fluid to articular cartilage and subchondral bone at different stages of osteoarthritis in a live mouse model","authors":"Mengcun Chen ,&nbsp;Yanmei Yang ,&nbsp;Mingshu Cui ,&nbsp;Bin Wang","doi":"10.1016/j.jot.2025.04.012","DOIUrl":"10.1016/j.jot.2025.04.012","url":null,"abstract":"<div><h3>Objective</h3><div>This study aims to (1) identify a simplified method to preserve sample integrity and maintain original fluorescence distribution; (2) assess the diffusivity of small and large molecules within articular cartilage (AC), calcified cartilage (CC), and subchondral bone (SB); and (3) investigate the changes in solute transport at various stages of osteoarthritis (OA) in a destabilization of the medial meniscus (DMM) murine model.</div></div><div><h3>Methods</h3><div>Fluorescent dyes of small and large molecules were injected into the knee joints of live mice. Joints were harvested and rapidly frozen immediately post-euthanasia. Optimal dye concentrations and dwelling times were determined through exploratory studies. Mice underwent either DMM or sham surgery and were evaluated at 2 and 8 weeks postoperatively. Relative fluorescence intensity was quantified within the AC, CC and SB, complemented by micro-CT, safranin O staining, and collagen II immunohistochemistry staining.</div></div><div><h3>Results</h3><div>The methodology successfully preserved sample integrity and original dye distribution. Fluorescent imaging revealed that small solute was mainly restricted by the tidemark, while large solute showed limited permeability in AC. Permeability of AC remained elevated in the DMM group at both time points. Increased permeability in CC and SB was observed only at 8 weeks post-DMM surgery, accompanied by reduced collagen II amount.</div></div><div><h3>Conclusions</h3><div>In live mice, the tidemark serves as a barrier to small molecule diffusion, while the cartilage surface restricts larger molecules; however, both structures exhibit increased permeability in OA. These findings advance the understanding of OA pathogenesis and suggest potential therapeutic targets related to cartilage permeability.</div></div><div><h3>Translational Potential</h3><div>The findings of this study advance the understanding of osteoarthritis pathogenesis by elucidating the role of solute transport alterations in cartilage and subchondral bone, thereby suggesting potential therapeutic targets aimed at modulating cartilage permeability to improve joint health in osteoarthritis.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 291-300"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scleraxis-expressing progenitor cells are critical for the maturation of the annulus fibrosus and demonstrate therapeutic potential","authors":"Hongtao Jia ,&nbsp;Shuqin Chen ,&nbsp;Xuye Hu ,&nbsp;Jiajun Wang ,&nbsp;Jinlong Suo ,&nbsp;Sheng-Ming Dai ,&nbsp;Weiguo Zou ,&nbsp;Heng Feng","doi":"10.1016/j.jot.2025.04.009","DOIUrl":"10.1016/j.jot.2025.04.009","url":null,"abstract":"<div><h3>Background</h3><div>Annulus fibrosus (AF) is an important part of the intervertebral disc (IVD) and its injury leads to back pain and impaired mobility. The stem/progenitor cells are essential for the maturation and repair of the AF, however, the identity of AF stem/progenitor cells remain elusive.</div></div><div><h3>Methods</h3><div>In this study, we sorted cells from the murine IVDs and performed the single-cell RNA sequencing. Using single-cell transcriptomics, genetic lineage tracing, <em>in vitro</em> stem cell experiment, ablation models and cell transplantation, we elucidate the role of AF progenitor cells in maturation and injury.</div></div><div><h3>Results</h3><div>On the basis of single-cell RNA-sequencing (scRNA-seq) analysis of the intervertebral disc, we found that the transcription factor <em>Scleraxis</em> (<em>Scx</em>) can specifically label a progenitor cell population of the outer AF. By lineage tracing assay, <em>Scx</em>-lineage AF cells proliferate mainly prior to sexual maturity, but barely proliferate after age of 8 weeks. The <em>Scx</em>-expressing AF cells are enriched for stem/progenitor cell markers and show a higher proliferative capacity and differentiation potential than the <em>Scx</em>⁻ cells. The ablation of <em>Scx</em>-expressing AF cells impairs the maturation of AF. The <em>Scx</em>⁺ AF cells are enriched for TGFβ signaling. Transplantation of <em>Scx</em>-lineage cells to injured AF with Connective tissue growth factor (CTGF) improved the AF healing.</div></div><div><h3>Conclusions</h3><div><em>Scleraxis</em>-expressing progenitor cells are critical for the maturation of AF and demonstrate therapeutic potential for AF regeneration.</div></div><div><h3>The translational potential of this article</h3><div>These findings expand the important role of stem cells in maturation and repair and provide new strategy for cellular therapy of AF repair.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 301-312"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiology and disease burden of fractures in Asia, 1990–2021: An analysis for the Global Burden of Disease Study 2021","authors":"Yechao Shen ,&nbsp;Boren Tan ,&nbsp;Jiahao Zhang ,&nbsp;Ning Zhang ,&nbsp;Zhan Wang","doi":"10.1016/j.jot.2025.04.001","DOIUrl":"10.1016/j.jot.2025.04.001","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;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).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;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}

{"title":"From “academic success” to “commercial success” —The model of medical device translation driven by SCI articles","authors":"Cheng-Kung Cheng ,&nbsp;Chengyan Lin ,&nbsp;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}

{"title":"Neuromuscular electrical stimulation alleviates stroke-related sarcopenia by promoting satellite cells myogenic differentiation via AMPK-ULK1-Autophagy axis","authors":"Xingdong Xiang ,&nbsp;Lei Huang ,&nbsp;Wenchen Luo ,&nbsp;Lieyang Qin ,&nbsp;Mengxuan Bian ,&nbsp;Weisin Chen ,&nbsp;Guanjie Han ,&nbsp;Ning Wang ,&nbsp;Guokang Mo ,&nbsp;Cheng Zhang ,&nbsp;Yongxing Zhang ,&nbsp;Huilin Yang ,&nbsp;Shunyi Lu ,&nbsp;Jian Zhang ,&nbsp;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&amp;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}

{"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 ,&nbsp;Daiki Murata ,&nbsp;Chinatsu Azuma ,&nbsp;Kotaro Nishida ,&nbsp;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}

{"title":"SHP2-mediated ROS activation induces chondrocyte paraptosis in osteoarthritis and is attenuated by low-intensity pulsed ultrasound","authors":"Wenjie Hou ,&nbsp;Xingru Shang ,&nbsp;Xiaoxia Hao ,&nbsp;Chunran Pan ,&nbsp;Zehang Zheng ,&nbsp;Yiwen Zhang ,&nbsp;Xiaofeng Deng ,&nbsp;Ruimin Chi ,&nbsp;Jiawei Liu ,&nbsp;Fengjing Guo ,&nbsp;Kai Sun ,&nbsp;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}

{"title":"Therapeutic effect of edaravone on osteoarthritis: targeting NRF2 signaling and mitochondrial function","authors":"Chao Jiang ,&nbsp;Yuhang Gong ,&nbsp;Xinyu Wu ,&nbsp;Jiangjie Chen ,&nbsp;Yiyu Chen ,&nbsp;Jingyao Chen ,&nbsp;Fang Tang ,&nbsp;Zhiyu Fang ,&nbsp;Yuxuan Bao ,&nbsp;Jiajing Ye ,&nbsp;Zhangfu Wang ,&nbsp;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>^−/− 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>^−/− 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}