Journal of Orthopaedic Translation最新文献

{"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}

{"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 ,&nbsp;Songlin Li ,&nbsp;Yange Luo ,&nbsp;Shihao Li ,&nbsp;Ziyue Chu ,&nbsp;Weibo Zheng ,&nbsp;Xuezhou Li ,&nbsp;Qunshan Lu ,&nbsp;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}

{"title":"Dihydroartemisinin ameliorates hemarthrosis-induced cartilage degeneration by suppressing chondrocyte senescence via activation of Keap1-Nrf2 signaling pathway","authors":"Qinghe Zeng ,&nbsp;Yongjia Feng ,&nbsp;Haipeng Huang ,&nbsp;Kaiao Zou ,&nbsp;Wenzhe Chen ,&nbsp;Xuefeng Li ,&nbsp;Yuliang Huang ,&nbsp;Weidong Wang ,&nbsp;Wenhua Yuan ,&nbsp;Pinger Wang ,&nbsp;Peijian Tong ,&nbsp;Hongting Jin ,&nbsp;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>^{<em>−/−</em>} 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>^{<em>−/−</em>} 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}

{"title":"MAGI1 attenuates osteoarthritis by regulating osteoclast fusion in subchondral bone through the RhoA-ROCK1 signaling pathway","authors":"Jing Zhang ,&nbsp;Wenhui Hu ,&nbsp;Yuheng Li ,&nbsp;Fei Kang ,&nbsp;Xuan Yao ,&nbsp;Jianmei Li ,&nbsp;Shiwu Dong","doi":"10.1016/j.jot.2025.04.007","DOIUrl":"10.1016/j.jot.2025.04.007","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;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 &lt;em&gt;in vitro&lt;/em&gt; 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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;MAGI1 expression was significantly downregulated during RANKL-induced osteoclastogenesis &lt;em&gt;in vitro&lt;/em&gt;. 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&lt;sup&gt;+&lt;/sup&gt; 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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;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}

{"title":"Allografts promote skeletal regeneration of periprosthetic femoral bone loss","authors":"Simon von Kroge ,&nbsp;Constantin Schmidt ,&nbsp;Sebastian Butscheidt ,&nbsp;Malte Ohlmeier ,&nbsp;Michael Amling ,&nbsp;Frank Timo Beil ,&nbsp;Thorsten Gehrke ,&nbsp;Klaus Püschel ,&nbsp;Michael Hahn ,&nbsp;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 (R² = 0.94, <em>p &lt;</em> 0.001), while no association between the allograft time <em>in situ</em> and incorporation (R² = 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}

{"title":"Endowing implants surface with enhanced vascularization and osseointegration via presenting triple-functional peptides","authors":"Wenjie Liu ,&nbsp;Qing Wang ,&nbsp;Hao Liu ,&nbsp;Suqin He ,&nbsp;Hongxiang Wang ,&nbsp;Chengwei Xu ,&nbsp;Chaofan Jin ,&nbsp;Na Li ,&nbsp;Lianxin Li","doi":"10.1016/j.jot.2025.03.020","DOIUrl":"10.1016/j.jot.2025.03.020","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Titanium-based implants have demonstrated good mechanical properties and biocompatibility in clinical applications, however, their inherent low bioactivity and complex biological behaviors during the process of osseointegration have resulted in a high rate of long-term implant failure. Although the immobilization of highly bioactive peptides on the implant surface is an effective strategy to improve osseointegration, the existing mono- and bifunctional peptide-modified implant surfaces can hardly meet the needs of cell behavior regulation and tissue regeneration during the process of osseointegration, and there is an urgent need for the development of more efficient surface modification technologies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;In the present study, a multifunctional peptide-modified implant material, MPN@K6, was successfully prepared by linking one end of a tripeptide system (cell adhesion peptide RGD, osteogenic growth peptide OGP, and pro-angiogenic peptide ang), which possesses a specific biological function, to hexameric lysine, and constructing the tripeptide system on the surface of metal-polyphenol coatings (MPNs) by means of non-covalent interactions between the lysine and the polyphenol, and then the MPN@K6 - RGD/OGP/ang was used as a peptide modification. RGD/OGP/ang.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The MPN@K6-RGD/OGP/Ang coating not only supported the early adhesion and migration, late osteogenesis and mineralization of BMSCs, but also promoted the adhesion, migration and vascularization of HUVECs. RT-qPCR results showed that the hybrid peptide up-regulated the expression of key factors in angiogenesis and osteogenesis. In vivo testing further confirmed these findings, with the functional peptide coating being 1.5 to 2 times more effective at inducing new bone formation at an early stage than the other two-peptide combinations, confirming the effectiveness and superiority of the tripeptide synergistic modification strategy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The results showed that the MPN@K6 - RGD/OGP/ang-modified implant exhibited significant advantages at the cellular level compared to different combinations of bifunctional peptide-coated forms. It was able to promote early cell migration and adhesion more efficiently, significantly induced osteoblast differentiation and mineralization, and enhanced the level of local vascularization. In a rat bone defect animal model, the material demonstrated more excellent bone repair effects and achieved better bone healing results, confirming the effectiveness and superiority of the tripeptide synergistic modification strategy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;The trifunctional peptide coating (MPN@K6 - RGD/OGP/Ang) constructed in this paper has a mild preparation process, is biologically safe, facilitates large-scale production, has a positive effect on bone tissue repair, and has a great potential for cl","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 150-166"},"PeriodicalIF":5.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854859","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":"Application of biphasic mineralized collagen/polycaprolactone scaffolds in the repair of large load-bearing bone defects: A study in a sheep model","authors":"Meng-Xuan Yao ,&nbsp;Jing-Chuan Zheng ,&nbsp;Hai-Cheng Wang ,&nbsp;Hong-Zhi Lv ,&nbsp;Yi-Fan Zhang ,&nbsp;Yu-Qin Zhang ,&nbsp;Tai-Long Shi ,&nbsp;Yan-Ze Zhu ,&nbsp;Ying-Ze Zhang ,&nbsp;Xiu-Mei Wang ,&nbsp;Wei Chen","doi":"10.1016/j.jot.2025.03.014","DOIUrl":"10.1016/j.jot.2025.03.014","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;This study aims to evaluate the efficacy of biphasic mineralized collagen/polycaprolactone (bMC/PCL) scaffolds in repairing large load-bearing bone defects, particularly femoral defects, using a sheep model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The bMC/PCL scaffolds were prepared by combining porous mineralized collagen/polycaprolactone (pMC/PCL) with compact mineralized collagen/polycaprolactone (cMC/PCL). The scaffolds were characterized using scanning electron microscopy to observe the microstructure and compression testing to assess mechanical properties. Twenty female sheep were selected to create a 20 mm femoral defect model, divided into a blank group (no material implanted) and an experimental group (bMC/PCL scaffolds implanted), with 10 sheep in each group. Bone healing and lower limb functional recovery were assessed at 1 month, 3 months, and 6 months postoperatively using Lane-Sandhu scores and visual analog scale scores for lameness. Additionally, bone repair progress was analyzed through X-ray, Micro-CT, and histological analyses.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Compared with the blank group, the bMC/PCL scaffold group showed significant improvement in bone defect repair. At 3 and 6 months postoperatively, X-ray, Micro-CT scans, and histological staining indicated stable scaffold integration and gradual new bone formation. The Lane-Sandhu scores in the experimental group were 3.60 ± 0.548 and 4.00 ± 0.707 at 3 and 6 months, respectively, whereas the blank group experienced plate/screw breakage leading to fixation failure, with scores of 1, indicating better bone healing in the experimental group. The lameness scores in the experimental group were 2.71 ± 0.97 and 1.48 ± 0.86 at 3 and 6 months, respectively, significantly lower than those in the blank group (&lt;em&gt;p&lt;/em&gt; &lt; 0.0001 and &lt;em&gt;p&lt;/em&gt; = 0.0002). Micro-CT analysis showed that bone volume to tissue volume ratio increased from 28.07 ± 9.22 % to 62.02 ± 11.82 %, bone mineral density increased from 0.392 ± 0.032 g/cm&lt;sup&gt;3&lt;/sup&gt; to 0.583 ± 0.125 g/cm&lt;sup&gt;3&lt;/sup&gt;, trabecular thickness increased from 0.690 ± 0.224 mm to 1.049 ± 0.089 mm, and trabecular separation decreased from 2.766 ± 1.183 mm to 0.501 ± 0.268 mm at 3 and 6 months postoperatively.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This study evaluated the efficacy of bMC/PCL scaffolds in repairing large load-bearing bone defects. The bMC/PCL scaffolds demonstrated good bioactivity and mechanical properties, indicating promising clinical application prospects. Future studies should further verify the safety and efficacy of these scaffolds in a wider range of animal models to support their clinical application.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Significance statement&lt;/h3&gt;&lt;div&gt;The bMC/PCL scaffolds offer a promising solution for large femoral bone defects, with potential for clinical use in orthopedic and trauma surgeries.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;The applicatio","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 138-149"},"PeriodicalIF":5.9,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854842","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}