Journal of Orthopaedic Translation最新文献

{"title":"Growth factor independence 1 ameliorates osteoarthritis by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway","authors":"Xiaoyu Jin , Xunhao Wang , Siyu Xu , Nuo Xu , Ziwei Wang , Chunqing Hu , Wei Liu , Zhaofeng Zhang , Xiyu Liu , Jingjing Fan , Ruiyang Jiang , Rui Wu , Zhongyang Lv , Dongquan Shi","doi":"10.1016/j.jot.2025.07.003","DOIUrl":"10.1016/j.jot.2025.07.003","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is the most common degenerative joint disease, characterized by cartilage deterioration, which is closely associated with chondrocyte ferroptosis. The aim of this study was to investigate the role and mechanism of previously unexplored gene, growth factor independence 1 (<em>Gfi1</em>) in chondrocyte ferroptosis, in order to provide a new therapeutic target for OA.</div></div><div><h3>Methods</h3><div>The expression of ferroptotic hallmarks and Gfi1 were analyzed in human and mice OA cartilages and tert-butyl hydroperoxide (TBHP)-induced primary chondrocytes. Small interfering RNA or overexpression plasmids were used to knock down or overexpress <em>Gfi1</em> to explore its role in chondrocyte ferroptosis and metabolism. Then, the role of Gfi1 in destabilization of medial meniscus (DMM) surgery-induced mice OA model was investigated with or without the intra-articular injection of adeno-associated virus-overexpressing <em>Gfi1</em> (AAV-<em>Gfi1</em>). Furthermore, RNA sequencing analysis was performed to reveal the key downstream pathway of Gfi1 exerting its role in chondrocyte ferroptosis.</div></div><div><h3>Results</h3><div>The expression of Gfi1 was significantly decreased, while 4-HNE, a typical lipid peroxidation product, was significantly increased both in damaged human and DMM surgery-induced mice OA cartilages. Consistently, Gfi1 was remarkably downregulated in TBHP-induced ferroptotic chondrocytes. Moreover, <em>Gfi1</em> knockdown aggravated chondrocyte ferroptosis by elevated levels of ferroptotic hallmarks, including total ROS, lipid ROS and Fe<sup>2+</sup> accumulation. The upregulation of ferroptotic driver (Cox2, Acsl4) and catabolic marker (Mmp13) and downregulation of ferroptotic suppressors (Gpx4, Fth1, Slc7a11) and anabolic marker (Col II) were also observed in TBHP-induced chondrocytes by <em>Gfi1</em> knockdown. On the contrary, <em>Gfi1</em> overexpression showed anti-ferroptotic effect in TBHP-induced chondrocytes. Intra-articular injection of AAV-<em>Gfi1</em> evidently alleviated cartilage degeneration by resisting ferroptosis and preserving the anabolism-catabolism homeostasis in OA cartilages. Comprehensive evaluation of subchondral bone sclerosis, osteophyte formation, synovitis and behavior performance further validated that <em>Gfi1</em> overexpression ameliorated OA progression. Mechanistically, MAPK signaling pathway was identified as the key downstream mediator of Gfi1 exerting anti-ferroptotic role in OA.</div></div><div><h3>Conclusion</h3><div>Gfi1 is downregulated in OA and its overexpression ameliorates OA progression by inhibiting chondrocyte ferroptosis via inactivation of MAPK signaling pathway.</div></div><div><h3>The translational potential of this article</h3><div>This study identifies Gfi1 as a novel therapeutic anti-ferroptotic target for cartilage degeneration, providing more clues for optimizing OA treatment strategies in clinical practice.</div></di","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 101-114"},"PeriodicalIF":5.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of exercise on pain and anxiety following rotator cuff injury: the role of paraventricular nucleus synaptic plasticity","authors":"Shen Liu ,&nbsp;Tingmo Huang ,&nbsp;Liyang Wan ,&nbsp;Yinghong Xiong ,&nbsp;Liyue Zeng ,&nbsp;Ruixue Du ,&nbsp;Ziyang Lin ,&nbsp;Zilong Guo ,&nbsp;Hongbin Lu ,&nbsp;Daqi Xu","doi":"10.1016/j.jot.2025.07.002","DOIUrl":"10.1016/j.jot.2025.07.002","url":null,"abstract":"<div><h3>Background</h3><div>Rotator cuff injury (RCI) often leads to chronic pain and anxiety, yet the underlying neural mechanisms remain unclear. This study explored central mechanisms linking RCI to these symptoms and assessed treadmill exercise (TE) as a therapeutic intervention in mice.</div></div><div><h3>Methods</h3><div>Male C57BL/6 mice underwent RCI surgery and were randomized into Sham, RCI, or TE groups (TE initiated on postoperative day 7). Mechanical hypersensitivity and anxiety-like behaviors were evaluated via von Frey, elevated plus maze, and open field tests. Synaptic plasticity proteins and structures in the paraventricular nucleus (PVN) were analyzed using immunofluorescence, Western blotting, electron microscopy, and Golgi staining. The brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) pathway's role was tested using the TrkB inhibitor ANA-12.</div></div><div><h3>Results</h3><div>RCI elicited notable alterations in synaptic structure within the PVN, characterized by decreased synaptophysin expression, increased growth-associated protein 43 expression, and synaptic microstructural abnormalities. These synaptic modifications were correlated with the manifestation of hyperalgesia and anxiety-like behaviors in murine models. TE reversed these synaptic changes and improved pain and anxiety symptoms. Mechanistically, TE activated the BDNF-TrkB signaling pathway in the PVN, which was essential for its therapeutic effects. Pharmacological blockade of the TrkB receptor using ANA-12 attenuated the therapeutic benefits of TE, confirming the critical role of BDNF-TrkB signaling pathway.</div></div><div><h3>Conclusion</h3><div>TE mitigates RCI-related pain and anxiety by restoring PVN synaptic plasticity via BDNF-TrkB signaling, underscoring exercise's therapeutic potential.</div></div><div><h3>The translational potential of this article</h3><div>The study reveals new insights into the central neural mechanisms of pain and anxiety after RCI, highlighting synaptic plasticity changes in the PVN. It clarifies the link between peripheral injury and central nervous system alterations, guiding clinicians toward more targeted and effective treatments.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 77-90"},"PeriodicalIF":5.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiological profiles and intervention strategies of limb deformities in China: A nationwide study based on the largest orthopedic database in China","authors":"Baofeng Guo ,&nbsp;Sihe Qin ,&nbsp;Junming Zhang ,&nbsp;Yilan Wang ,&nbsp;Lei Shi","doi":"10.1016/j.jot.2025.07.005","DOIUrl":"10.1016/j.jot.2025.07.005","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Limb deformities are almost associated with varying degrees of disability, which severely affects the quality of life and social participation. However, the epidemiological profiles of limb deformities remain underreported. As the world's largest developing country with regional economic disparities, China faces unique challenges in the diagnosis and management of limb deformities. The Qin Sihe Orthopaedic Surgery Database is currently the most comprehensive database of limb deformity in China, which has the largest case volume, the widest disease spectrum, and the broadest geographical coverage, provides an invaluable resource for studying limb deformity patterns in China and other developing countries.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;To analyze 37763 limb deformity cases from the Qin Sihe Orthopaedic Surgery Database, and to summarize the etiology distribution, disease spectrum, gender, age, geographical distribution, gait abnormalities and treatment strategies of limb deformities in China.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Descriptive epidemiological methods were used to analyze the data of Qin Sihe Orthopaedic Surgery Database from May 25th, 1978 to December 31st, 2023 containing 37763 cases of Limb deformities. The data on patients' gender, age, etiology distribution, disease spectrum, geographical distribution, gait abnormalities and surgical methods etc will be statistically analyzed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Among 37763 patients, 21815 (57.77 %) were male and 15948 (42.23 %) were female, aged 1–84 years old, covering 33 provinces, municipalities and autonomous regions in China and some international regions. Etiologies included 239 neurogenic, traumatic, congenital and metabolic diseases, among which neurogenic diseases took the dominant portion: 24430 (64. 7 %) cases of post-polio sequelae, 5088 (13. 4 %) cases of cerebral palsy. Lower limb deformities(35,869 cases,95 %) was significantly more than upper limb deformities (646 cases, 1.7 %). The surgical interventions included soft tissue release and tendon lengthening (e. g. Achilles tendon lengthening, 8282 cases, 21.93 %), osteotomy (e.g. supracondylar femoral osteotomy, 7740 cases, 20.50 %), and arthrodesis (e. g. talocalcaneal arthrodesis, 6873 cases, 18.20 %). The fixation methods included Ilizarov external fixation (5611 cases), combined external fixation (5612 cases), combined internal fixation (1805 cases) and plaster or brace immobilization (24735 cases).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;The causes of limb deformities in China are diverse, and the diseases involves multiple disciplines. Cases are predominantly male and young., Polio sequelae deformity remains the main malformation diseases, but the proportion of cerebral palsy, limb deformities after trauma, lower limb deformities after spina bifida and genetic metabolic diseases are increasing. This study provides important real-world data for the classification of etiol","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 91-100"},"PeriodicalIF":5.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTHrP buffers Wnt/β-catenin activity through a PKC-ζ involved negative feedback loop to maintain articular cartilage homeostasis and attenuate osteoarthritis","authors":"W.X. Tong,&nbsp;H.J. Chen,&nbsp;Z.L. Huang,&nbsp;D. Zhao,&nbsp;J. Hu","doi":"10.1016/j.jot.2025.03.012","DOIUrl":"10.1016/j.jot.2025.03.012","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. The Wnt/β-catenin cascade is essential in articular cartilage development and homeostasis. Interruption of β-catenin (either overexpression or inhibition) leads to cartilage degeneration. However, the mechanism for stabilizing Wnt/β-catenin remains unclear.</div></div><div><h3>Methods</h3><div>We established the mouse destabilization of the medial meniscus (DMM) OA model and analyzed the clinical specimens to detect Wnt/β-catenin and PTHrP. The chondrocytes were isolated and treated with various cytokines including Wnt3a, Ihh, IL-1β, and PTHrP to reveal the molecular mechanism. Epigenetic and bioinformatic analyses were conducted to screen the key genes for the PTHrP regulation, and an Adeno-associated Virus (AAV) delivery system for PTHrP was established for OA gene therapy (prevention) application.</div></div><div><h3>Results</h3><div>We confirmed the Wnt/β-catenin activation and PTHrP suppression in cartilage in post-traumatic OA. Wnt/β-catenin further upregulated PTHrP expression through binding to its promoter (P2), and induced mRNA (AT6) transcript expression. Unexpectedly, PTHrP repressed Wnt/β-catenin activity and formed a Wnt/β-catenin-PTHrP negative feedback loop in very primary chondrocytes to maintain cartilage homeostasis. However, this negative feedback loop vanished in dedifferentiated chondrocytes, hypertrophic chondrocytes, and IL-1β treated primary chondrocytes. In these chondrocytes under pathological conditions, we further found that miR-106b-5p was increased and directly targeted PTHrP mRNA to abolish the feedback loop. Using Bulk RNA-seq and KEGG analysis, we screened and confirmed that PKC-ζ was activated by PTHrP through phosphorylation at Thr410/403, and subsequently induced β-catenin phosphorylation, ubiquitination and degeneration. Finally, we disclosed that exogenous PTHrP attenuated OA progression.</div></div><div><h3>Conclusion</h3><div>This study reveals that PTHrP is a vital mediator in keeping Wnt/β-catenin homeostasis through a negative feedback loop similar to its role in balancing the Ihh pathway activity in the secondary ossification center and growth plate.</div></div><div><h3>The translational potential of this article</h3><div>These findings highlight that PTHrP might be a therapeutic target for attenuating cartilage degeneration and OA process by the gene therapy approach.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 65-76"},"PeriodicalIF":5.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting periprosthetic joint Infection: Evaluating supervised machine learning models for clinical application","authors":"Serban Dragosloveanu ,&nbsp;Diana Elena Vulpe ,&nbsp;Constantin Adrian Andrei ,&nbsp;Dana-Georgiana Nedelea ,&nbsp;Nicolae Dragos Garofil ,&nbsp;Cătălin Anghel ,&nbsp;Christiana Diana Maria Dragosloveanu ,&nbsp;Romica Cergan ,&nbsp;Cristian Scheau","doi":"10.1016/j.jot.2025.06.016","DOIUrl":"10.1016/j.jot.2025.06.016","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Periprosthetic joint infection (PJI) is a serious complication that can occur after joint arthroplasty, such as hip or knee replacement surgeries. It involves the invasion of the periprosthetic space by pathogens, leading to severe inflammation and often requiring complex medical intervention. PJI is associated with significant morbidity, increased healthcare costs, and a reduced quality of life for patients. This study aims to evaluate the performance of multiple supervised machine learning models in predicting PJI using clinical and demographic data collected from patients who underwent joint arthroplasty.</div></div><div><h3>Methods</h3><div>Eight supervised machine learning models—Logistic Regression, Random Forest, XGBoost, Artificial Neural Network (ANN), k-Nearest Neighbors (KNN), AdaBoost, Gaussian Naive Bayes (GNB), and Stochastic Gradient Descent (SGD)—were trained and tested on a dataset of 27,854 patients. Models were evaluated using accuracy, precision, recall, specificity, F1 score, and area under the ROC curve (AUC).</div></div><div><h3>Results</h3><div>Random Forest and XGBoost showed the best overall performance, with high accuracy and balanced metrics across all evaluation criteria. KNN also performed strongly, particularly in minimizing misclassifications. GNB and SGD yielded weaker results, with higher error rates.</div></div><div><h3>Conclusion</h3><div>Random Forest, XGBoost, and KNN are the most promising models for clinical implementation in PJI prediction. Their robust performance may support earlier diagnosis and improved patient outcomes in orthopedic care.</div></div><div><h3>Translational potential statement</h3><div>This study demonstrates that machine learning models—particularly Random Forest and XGBoost—can accurately predict periprosthetic joint infection (PJI) using structured electronic health record data. By integrating these models into preoperative assessment workflows, clinicians may be able to identify high-risk patients earlier, personalize prophylactic strategies, and reduce infection-related morbidity. The implementation of these predictive tools has the potential to enhance clinical decision-making, improve surgical outcomes, and optimize the use of healthcare resources in orthopedic practice.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 51-64"},"PeriodicalIF":5.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synovial organoids: From fundamental construction to groundbreaking applications in arthritic disorders","authors":"Xin Jin ,&nbsp;Lin Huang ,&nbsp;Xueyan Wang ,&nbsp;Yun Tan ,&nbsp;Miao Huang ,&nbsp;Haijing Fu ,&nbsp;Chengping Wen ,&nbsp;Mingqian Zhou","doi":"10.1016/j.jot.2025.07.004","DOIUrl":"10.1016/j.jot.2025.07.004","url":null,"abstract":"<div><div>As an emerging three-dimensional (3D) cell culture model, synovial organoids can highly mimic the structure and function of synovial tissue in vivo, providing a new and powerful tool for the research of synovial-related diseases. This article elaborated in detail on the construction of synovial organoids from the cell sources, culture systems, and construction techniques. Meanwhile, it comprehensively reviewed the application progress of synovial organoids in arthritic diseases including rheumatoid arthritis and osteoarthritis such as disease pathogenesis, drug development, and personalized therapy. Additionally, it explores current challenges and future directions for synovial organoids, providing a reference for further research and applications in related-diseases.</div><div>The Translational Potential of this Article</div><div>Synovial organoids enable direct modeling of the human synovial joint, offering a physiologically relevant platform for high-throughput drug screening. Patient-derived organoids not only facilitate the development of personalized medicine but also reduce reliance on animal studies for preclinical validation. This approach addresses ethical challenges and species-specific limitations while enhancing the translational relevance to human disease mechanisms.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 26-36"},"PeriodicalIF":5.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction of organoids using bioprinting technology: a frontier exploration of cartilage repair","authors":"Jingtao Huang ,&nbsp;Shicheng Jia ,&nbsp;Rongji Liang ,&nbsp;Aikang Li ,&nbsp;Lin Li ,&nbsp;Haojian Wang ,&nbsp;Jiayou Chen ,&nbsp;Haoxian Tang ,&nbsp;Xuan Zhang ,&nbsp;Jianjing Lin ,&nbsp;Xintao Zhang","doi":"10.1016/j.jot.2025.06.020","DOIUrl":"10.1016/j.jot.2025.06.020","url":null,"abstract":"<div><div>Articular cartilage defects caused by trauma or degeneration severely impair patient function. Cartilage repair organoids represent a transformative approach in regenerative medicine to address these challenges. This review focuses on the development and therapeutic potential of such organoids, detailing their role in overcoming limitations of conventional treatments. Central to this progress, bioprinting technology enables precise organoid fabrication by advancing organoid-compatible bioinks and printing techniques. We further examine applications in disease modeling and drug screening, alongside pathways for clinical translation. As organoid engineering matures, it promises to deliver effective, patient-specific solutions for cartilage restoration.</div><div>The Translational Potential Statement: The Translational Potential of this Article: 3D-bioprinted cartilage organoids exhibit outstanding efficacy in animal models and hold promise for future clinical trials. The bioinks and printing technologies are distilled to promote basic research toward translation of cartilage repair.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 37-50"},"PeriodicalIF":5.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144634441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress activates YAP/TEAD1/NCOA4 axis to promote ferroptosis of endplate chondrocytes and aggravate intervertebral disc degeneration","authors":"Heran Wang ,&nbsp;Xiaodong Liu ,&nbsp;Xingzhi Jing ,&nbsp;Bofei Zhang ,&nbsp;Xin Liu ,&nbsp;Xiaoyang Liu ,&nbsp;Fei Jia ,&nbsp;Cheng Su ,&nbsp;Wenchao Wang ,&nbsp;Xingang Cui","doi":"10.1016/j.jot.2025.07.001","DOIUrl":"10.1016/j.jot.2025.07.001","url":null,"abstract":"<div><h3>Background</h3><div>Intervertebral disc degeneration (IDD) is a major cause of low back pain, with cartilaginous endplate (CEP) degeneration playing a critical role. While Yes-associated protein (YAP) and its involvement in CEP degeneration and ferroptosis remain unclear. This study aimed to investigate the regulatory role of YAP in CEP ferroptosis and its underlying mechanisms.</div></div><div><h3>Methods</h3><div>YAP expression was analyzed in human CEP tissues and mouse LSI models. CEP cells were treated with Verteporfin or YAP-siRNA. Ferroptosis was assessed by measuring iron levels, lipid peroxidation, GSH content, and viability assays. Molecular mechanisms were elucidated using CUT&amp;RUN-qPCR, dual-LUC, and immunofluorescence colocalization. Verteporfin (VP) therapeutic efficacy was evaluated in LSI mice.</div></div><div><h3>Results</h3><div>YAP knockdown attenuated oxidative stress-induced CEP chondrocyte degeneration and ferroptosis features. Mechanistically, we identified that oxidative stress-induced CEP chondrocyte degeneration involves ferritinophagy, which is regulated by the YAP/TEAD1 signaling axis through transcriptional control of nuclear coactivator 4 (NCOA4). Treatment with verteporfin, a YAP/TEAD1 axis inhibitor, effectively reduced CEP chondrocyte degeneration and IDD progression by targeting NCOA4-mediated ferritinophagy.</div></div><div><h3>Conclusion</h3><div>Through detailed molecular and cellular analyses, we revealed that the YAP/TEAD1/NCOA4 signaling axis plays a crucial role in regulating CEP chondrocyte ferroptosis and IDD development. These findings not only enhance our understanding of IDD pathogenesis but also suggest that targeting the YAP/TEAD1/NCOA4 axis could be a promising therapeutic strategy for treating IDD.</div></div><div><h3>The Translational Potential of this Article</h3><div>This study reveals YAP as a novel therapeutic target for intervertebral disc degeneration by regulating ferroptosis in cartilage endplate cells, which provides a novel strategy in the prevention of IDD.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 8-25"},"PeriodicalIF":5.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604130","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":"High-dose romosozumab promoted bone regeneration of critical-size ulnar defect filled with demineralized bone matrix in nonhuman primates","authors":"Xiaodong Li ,&nbsp;Frank Asuncion ,&nbsp;Michael Ominsky ,&nbsp;Qing-Tian Niu ,&nbsp;Kristina E. Akesson ,&nbsp;Jeffrey Wang ,&nbsp;Jay Lieberman ,&nbsp;Hua Zhu Ke","doi":"10.1016/j.jot.2025.06.019","DOIUrl":"10.1016/j.jot.2025.06.019","url":null,"abstract":"<div><h3>Background</h3><div>Large bone defects are challenging to manage clinically and usually require treatment with bone graft or bone graft substitute. This study evaluated the effect of romosozumab, a sclerostin antibody, in combination with demineralized bone matrix (DBM) on bone regeneration in a critical-size ulnar defect model in nonhuman primates.</div></div><div><h3>Methods</h3><div>In cynomolgus monkeys (N = 22, male, 10–12 years old), a full-cortex bone defect (0.5 cm long) was created in the left ulnar shaft and filled with DBM. Animals were randomized to receive vehicle (n = 10) or romosozumab (n = 12; 30 mg/kg) subcutaneously, every 2 weeks for 28 weeks. Radiographs of the left ulna were taken every 2 weeks for 28 weeks to monitor bone regeneration response. Ulnae were excised and analyzed by ex-vivo x-ray and micro-computed tomography (micro-CT) to evaluate bone repair, and lumbar vertebrae were excised for bone histomorphometric analysis to evaluate the systemic anabolic response.</div></div><div><h3>Results</h3><div>In-vivo and ex-vivo x-ray images of surgical ulnae demonstrated that the critical-size ulnar defect fully bridged in 3 romosozumab-treated monkeys at week 28 but not in any vehicle-treated monkey. Micro-CT analysis demonstrated that average new bone volume and new bone area within the defect region were 118 % and 105 % greater, respectively, with romosozumab versus vehicle. Trabecular bone volume per tissue volume and trabecular thickness of lumbar vertebral body were 72 % and 92 % greater, and eroded surface was significantly lower with romosozumab versus vehicle.</div></div><div><h3>Conclusion</h3><div>High-dose romosozumab in combination with DBM improved bone regeneration in a critical-size ulnar defect model and increased bone mass in non-surgical bone in nonhuman primates.</div></div><div><h3>The translational potential of this article</h3><div>Clinical management of large bone defect is complex and challenging. More effective management is needed. This paper reports the first nonhuman primate study that evaluated high-dose romosozumab in combination with demineralized bone matrix in a critical-size defect model and provides perspective for the future research evaluating the combination of romosozumab and bone graft or bone graft substitutes in various relevant clinical conditions.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 1-7"},"PeriodicalIF":5.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588187","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":"Bone organoid construction and evolution","authors":"Yang Hong ,&nbsp;Ruiyang Li ,&nbsp;Shihao Sheng ,&nbsp;Fengjin Zhou ,&nbsp;Long Bai ,&nbsp;Jiacan Su","doi":"10.1016/j.jot.2025.06.011","DOIUrl":"10.1016/j.jot.2025.06.011","url":null,"abstract":"<div><div>Organoids, generated through three-dimensional in vitro culture, are cellular aggregates that accurately mimic the complex microenvironment, cell–cell interactions, and signaling mechanisms of native tissues. These models offer transformative advantages in studying disease mechanisms, drug screening, and personalized medicine. Compared to traditional two-dimensional cell cultures and animal models, organoid systems exhibit higher physiological relevance, effectively mitigating species-specific discrepancies while significantly enhancing clinical translational feasibility. However, current organoid research primarily focuses on soft tissues such as the heart, liver, spleen, lungs, and kidneys, with limited progress in hard tissue organoids, particularly bone organoids. Given the pivotal role of bone tissue in clinical bone repair, disease mechanism elucidation, and drug screening, this field demands further investigation. Based on our previous research, this review introduces a five-stage iterative framework for bone organoid development: 1.0 (physiological model), 2.0 (pathological model), 3.0 (structural model), 4.0 (composite model), and 5.0 (applied model). This paper systematically reviews the technical pathways for bone organoid construction, highlights the core features and scientific value of each model iteration, and explores the current challenges and future directions in this emerging field. The goal is to provide theoretical and technological insights that advance bone organoid research, offering innovative solutions for bone-related disease studies and clinical applications.</div><div>The translational potential of this article: This review provides a systematic overview of bone organoid development, highlighting their remarkable role in orthopaedic research and in clinical practice. Through the incorporation of advanced technologies like artificial intelligence and 3D bioprinting, bone organoids provide novel approaches to the development of regenerative medicine and customized orthopaedic treatments.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 260-273"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534722","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}