Journal of Orthopaedic Translation最新文献

{"title":"Inhibition of ERK1/2 mediated activation of Drp1 alleviates intervertebral disc degeneration via suppressing pyroptosis and apoptosis in nucleus pulposus cells","authors":"Shenkai Su ,&nbsp;Xuanzhang Wu ,&nbsp;Bin Li ,&nbsp;Fengyu Zhang ,&nbsp;Kaiying Zhang ,&nbsp;Hui Wang ,&nbsp;Yan Lin ,&nbsp;Jiaoxiang Chen","doi":"10.1016/j.jot.2025.01.013","DOIUrl":"10.1016/j.jot.2025.01.013","url":null,"abstract":"<div><h3>Objective</h3><div>Dynamin-related protein 1 (Drp1) plays a crucial role in various inflammatory and degenerative diseases, yet its involvement in intervertebral disc degeneration (IVDD) remains poorly understood. This study aims to elucidate the mechanism by which Drp1 contributes to IVDD and to identify the efficacy of the Drp1 inhibitor Mdivi-1 on IVDD.</div></div><div><h3>Methods</h3><div>Tert-butyl hydroperoxide (TBHP) is utilized to induce an oxidative stress microenvironment <em>in vitro</em>. <em>In vivo</em>, IVDD model is constructed in 8-week old rats through puncture operation. The therapeutic effect of Mdivi-1 is evaluated through X-ray, MRI and histological analysis. A comprehensive set of experiments, including single-cell sequencing analysis, western blot, flow cytometry and immunofluorescence staining, are conducted to investigate the role and underlying mechanisms of Drp1 <em>in vitro</em>.</div></div><div><h3>Results</h3><div>Our study demonstrates that the expression of Drp1 and phosphorylated Drp1 (p-Drp1) are up-regulated in degenerative nucleus pulposus cells (NPCs), which are accompanied with increased pyroptosis and apoptosis. <em>In vivo</em>, both si-Drp1-mediated Drp1 knockdown and the pharmacological inhibitor Mdivi-1 alleviate puncture-induced IVDD in rats. <em>In vitro</em>, si-Drp1 or Mdivi-1 inhibits mitochondria-dependent apoptosis and pyroptosis triggered by TBHP. Mechanistically, Mdivi-1 reduces p-Drp1 levels, inhibits excessive mitochondrial fission, and mitigates mitochondrial dysfunction. Drp1 phosphorylation-based Drp1 mitochondrial translocation and subsequent apoptosis and pyroptosis are regulated by ERK1/2 phosphorylation in NPCs under oxidative stress condition.</div></div><div><h3>Conclusion</h3><div>This study highlights the involvement of Drp1 in the pathological progression of degenerative NPCs in IVDD, which is regulated by ERK1/2. Pharmacological inhibition of Drp1 with Mdivi-1 protects NPCs by promoting mitochondrial function and attenuating apoptosis and pyroptosis. These findings suggest that Mdivi-1 is a promising therapeutic candidate for IVDD treatment.</div></div><div><h3>Translational Potential</h3><div>By offering experimental evidence on the role and mechanism of Drp1 in IVDD, this study underscores the potential of Mdivi-1 as a therapeutic strategy for IVDD.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 163-175"},"PeriodicalIF":5.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hip joint-preserving strategies for treating osteonecrosis of the femoral head: From nonoperative to operative procedures","authors":"Tanqiu Qi ,&nbsp;Yan Yan ,&nbsp;William Qi ,&nbsp;Weiheng Chen ,&nbsp;Haisheng Yang","doi":"10.1016/j.jot.2025.02.001","DOIUrl":"10.1016/j.jot.2025.02.001","url":null,"abstract":"<div><div>Osteonecrosis of the femoral head (ONFH) has an exceedingly high prevalence and disability rate, causing a tremendous socioeconomic burden. The prevalence of ONFH is increasing, while the population of the patients with ONFH is becoming younger. Once the femoral head collapses, treatment becomes difficult and often requires a hip joint replacement, which is not favorable for young patients. Therefore, hip joint-preserving treatments at an early stage of ONFH are particularly important. This study provides a comprehensive review on hip-preserving strategies for treating ONFH, including nonoperative treatments (e.g., protective weight bearing, hyperbaric oxygen, pulsed electromagnetic, extracorporeal shockwave, bisphosphonate, anticoagulants, hypolipidemics, vasodilators, and traditional Chinese medicine) and operative treatments (e.g., core decompression, osteotomy, bone grafting, mesenchymal stem cell transplantation, tantalum rods, and tissue engineering). Nonoperative treatments aim to slow down the progression of the disease and delay the need for joint replacement; however, they usually cannot effectively prevent the progression of the disease, except in cases of small necrosis areas (&lt;10 %). Additionally, nonoperative treatments have unclear mechanisms that require further investigation. In contrast, operative treatments may stop the negative outcomes of necrosis and therefore appear to be more promising. Currently, an emerging area in operative treatments is regenerative medicine, which could promote the generation of bone tissues and blood vessels and restore hip joint function to pre-necrotic levels as much as possible. This review seeks to not only provide an important reference for clinicians when choosing appropriate strategies for treating ONFH but also offer certain guidance for future basic research in developing ONFH treatments.</div></div><div><h3>The translational potential of this article</h3><div>The incidence of ONFH is increasing, and patients are becoming younger on average. Therefore, the development of hip joint-preserving strategies to treat ONFH at earlier stages is urgently needed, particularly for young patients. However, a comprehensive review is lacking regarding the currently-available hip joint-preserving strategies and their effectiveness. This study is motivated to fill this gap and serve as an important reference for clinicians in choosing appropriate strategies to treat ONFH.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 256-277"},"PeriodicalIF":5.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143644318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JP4-039 protects chondrocytes from ferroptosis to attenuate osteoarthritis progression by promoting Pink1/Parkin-dependent mitophagy","authors":"Ya Xie ,&nbsp;Zhongyang Lv ,&nbsp;Weitong Li ,&nbsp;JinTao Lin ,&nbsp;Wei Sun ,&nbsp;Hu Guo ,&nbsp;Xiaoyu Jin ,&nbsp;Yuan Liu ,&nbsp;Ruiyang Jiang ,&nbsp;Yuxiang Fei ,&nbsp;Rui Wu ,&nbsp;Dongquan Shi","doi":"10.1016/j.jot.2025.01.001","DOIUrl":"10.1016/j.jot.2025.01.001","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is the most common degenerative joint disease, and its main pathological mechanism is articular cartilage degeneration. The purpose of this study was to investigate the role of mitophagy in the pathogenesis of chondrocyte ferroptosis in OA.</div></div><div><h3>Methods</h3><div>The expressions of ferroptosis related proteins (GPX4, FTH1, COX2) and ubiquitin-dependent mitophagy related proteins (PARKIN, PINK1) in the intact and injured areas of OA cartilage were analyzed. Nitro oxide JP4-039, a mitochondrial targeting antioxidant, has bifunctional role of targeting mitochondria. Then we evaluated the potential protective effect of JP4-039 in OA using the destabilization of medial meniscus (DMM)-induced OA model, as well as tert-butyl hydrogen peroxide (TBHP)-treated primary mouse chondrocytes and human cartilage explants.</div></div><div><h3>Results</h3><div>The concentrations of iron and lipid peroxidation and the expression of ferroptosis drivers in the damaged areas of human OA cartilages were significantly higher than those in the intact cartilage. Pink1/Parkin-dependent mitophagy decreased in the injured area of human OA cartilage and was negatively correlated with ferroptosis. Then, the toxicity and effectiveness of JP4-039 are tested to determine its working concentration. Next, at the molecular biological level, we found that JP4-039 showed the effect of anti-chondrocyte ferroptosis. Moreover, it was verified on DMM-induced OA model mice, that JP4-039 could delay the progression of OA. Finally, JP4-039 was re-verified in vivo and in vitro to inhibit chondrocyte ferroptosis and delay the progression of OA by promoting Pink1/Parkin-dependent mitophagy.</div></div><div><h3>Conclusion</h3><div>JP4-039 inhibits ferroptosis of chondrocytes by promoting Pink1/Parkin-dependent mitophagy and delays OA progression.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 132-144"},"PeriodicalIF":5.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted activation on Bnip3 enhances mitophagy to prevent the progression of osteoarthritis","authors":"Yong Gou ,&nbsp;Chenggui Wang ,&nbsp;Kejian Fu ,&nbsp;Shenkai Su ,&nbsp;Hangjin Zhou ,&nbsp;Chunkai Bao ,&nbsp;Hui Nan ,&nbsp;Xiang Zhang ,&nbsp;Yiyuan Xu ,&nbsp;Qi Chen ,&nbsp;Xinchen Gu ,&nbsp;Baiting Chen ,&nbsp;Lin Zheng ,&nbsp;Chenglong Xie ,&nbsp;Man Zhang ,&nbsp;Enxing Xue ,&nbsp;Jiawei Li","doi":"10.1016/j.jot.2025.01.012","DOIUrl":"10.1016/j.jot.2025.01.012","url":null,"abstract":"<div><h3>Background</h3><div>The production of reactive oxygen species (ROS) and mitochondrial dysfunction in chondrocytes are closely related to cartilage degeneration in the procedure of osteoarthritis (OA). Mitophagy is responsible for the scavenging of ROS and dysfunctional mitochondria and is considered a key therapeutic target for the treatment of OA. Tiopronin, a classic thiol antioxidant, has been widely studied for the treatment of various oxidative stress-related diseases.</div></div><div><h3>Methods</h3><div>The expression of mitophagy (PINK1, PARKIN, and TOMM20) in intact and damaged cartilage of OA patients was analyzed by Western blot and histological analysis. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanism of tiopronin in regulating mitophagy in chondrocytes, and then to find the specific target of tiopronin. The therapeutic effects of tiopronin were evaluated in the OA model induced by destabilisation of the medial meniscus (DMM), chondrocytes degenerative model with the primary chondrocytes from mouse and human cartilage explants experiment. The downstream molecular mechanisms of tiopronin were further investigated by si-RNA knockdown of mitophagy-related proteins.</div></div><div><h3>Results</h3><div>The level of mitophagy in cartilage was negatively correlated with the severity of OA. We revealed that tiopronin promoted the anabolism of the extracellular matrix (ECM) of hyaline chondrocytes and alleviates ROS <em>in vitro</em> and <em>in vivo</em> by strengthening mitophagy. Moreover, tiopronin strongly activated the expression of Bnip3, a protein anchored in the mitochondrial membrane, and subsequently enhanced the Pink1/Parkin signaling pathway.</div></div><div><h3>Conclusion</h3><div>These findings indicate that the Bnip3-Pink1-Parkin signaling pathway, targeted and activated by tiopronin, plays a key role in inhibiting the progression of OA.</div></div><div><h3>The translational potential of this article</h3><div>As a classical drug in clinic, tiopronin was developed a new therapeutic approach in the treatment in OA via this study. Based the significant and efficient effect of tiopronin in inhibiting the cartilage degermation and delay the progression of OA, it was believed that tiopronin may become an effective therapeutic candidate for OA treatment in clinical settings</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 242-255"},"PeriodicalIF":5.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143644326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and function of periosteal skeletal stem cells in skeletal development, homeostasis, and disease","authors":"Fan Shi ,&nbsp;Guixin Yuan ,&nbsp;Zuoxing Wu ,&nbsp;Zhengqiong Luo ,&nbsp;Zihan Chen ,&nbsp;Qian Liu ,&nbsp;Na Li ,&nbsp;Ren Xu","doi":"10.1016/j.jot.2025.01.010","DOIUrl":"10.1016/j.jot.2025.01.010","url":null,"abstract":"<div><h3>Background</h3><div>Periosteum-resident skeletal stem cells (SSCs) are essential for the growth, maintenance, and repair of the skeletal system. These cells exhibit self-renewal ability and clonal pluripotency. Compared to the diverse bone marrow mesenchymal stem cells (BMSCs), periosteal skeletal stem cells (P-SSCs) represent a purified stem cell population and are preferable for bone tissue engineering.</div></div><div><h3>Methods</h3><div>This review covers the histological structure of the periosteum, process of isolating and characterising P-SSCs, and spatiotemporal distribution and characteristics of P-SSCs from different lineages. Additionally, the roles of P-SSCs in bone injury, disease, and periosteal niche regulation are discussed.</div></div><div><h3>Results</h3><div>Intramembrane and intraconal ossification of P-SSCs exhibits favourable therapeutic potential. Osteogenesis using P-SSCs is an ideal process for bone repair.</div></div><div><h3>Conclusions</h3><div>P-SSCs are vital for bone formation, maintenance, and repair. P-SSCs are essential components of the periosteal microenvironment. Therefore, it is essential to investigate their critical clinical applications and translational functions. By targeting and inducing endogenous stem cells, the in situ repair of bone defects can be facilitated, leading to the development of more effective novel therapies.</div></div><div><h3>The translational potential of this article</h3><div>To enhance our understanding of the function of P-SSCs in bone repair and skeleton-related diseases, it is imperative to elucidate the current research status of P-SSCs and ascertain the prospective trajectory for their advancement and refinement in bone tissue engineering. P-SSCs are expected to play an expanded role in treating bone abnormalities, leading to the optimisation of bone tissue treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 177-186"},"PeriodicalIF":5.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Internal fixation with biodegradable high purity magnesium screws in the treatment of ankle fracture","authors":"De-Wei Zhao ,&nbsp;Tian-Wei Zhang ,&nbsp;Wei-Dan Wang ,&nbsp;Zi-Ming Wang ,&nbsp;Fu-Yang Wang ,&nbsp;Xing Yang ,&nbsp;Rong-Hua Li ,&nbsp;Liang-Liang Cheng ,&nbsp;Yu Zhang ,&nbsp;Hui-Ya Wang ,&nbsp;Wang-Wei Zhu ,&nbsp;Shi-Bo Huang ,&nbsp;Wei-Rong Li ,&nbsp;Ling Qin","doi":"10.1016/j.jot.2025.01.005","DOIUrl":"10.1016/j.jot.2025.01.005","url":null,"abstract":"<div><h3>Background</h3><div>Metal plates and screws are widely used as internal fixations in the treatment of ankle fracture. However, there are many disadvantages such as \"stress shielding\" effect and the need for secondary surgical removal, which potentially affected the blood supply around the fracture site. In recent years, many studies confirmed that the biodegradable high purity magnesium (Mg) screws exhibited sufficient mechanical strength with adequate degradation rate for effective bone healing, avoiding the need for implant removal operations.</div></div><div><h3>Method</h3><div>We conducted a prospective study on patients with ankle fractures treated at Affiliated Zhongshan Hospital of Dalian University between January 2020 and January 2021. Twenty-four patients (twelve patients for each group) with ankle fractures were treated with high purity Mg screws or conventional titanium alloy plates and screws. Hematological examinations were performed in the early postoperative period, X-ray examinations were performed in the long-term postoperative follow-up. Postoperative complications, including infection, failure of internal fixation and malunion, were recorded during the follow-up. The visual analogue scale (VAS) was used to evaluate postoperative pain perceived by the patients, and the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot scoring system was used to evaluate their postoperative ankle function.</div></div><div><h3>Results</h3><div>All patients achieved good fracture alignment, and imaging examination showed that the biodegradable high purity Mg screws degraded gradually without breakage or displacement. None of the patients experienced infection, failure of internal fixation, malunion or other complications in both groups.</div></div><div><h3>Conclusion</h3><div>The results showed that biodegradable high purity Mg screws could be effectively used in the clinical treatment of ankle fractures, ensuring safety and satisfactory postoperative functional recovery.</div><div>The translational potential of this article: The biodegradable high purity Mg screws could provide sufficient mechanical strength and fixation stability for ankle fracture. Our study extended the clinical application of the biodegradable high purity Mg screws for fracture.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 198-206"},"PeriodicalIF":5.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cell related osteoimmunology in fracture healing: Potential targets for augmenting bone regeneration","authors":"Haixing Wang ,&nbsp;Yashi Li ,&nbsp;Haoxin Li ,&nbsp;Xu Yan ,&nbsp;Zhaowei Jiang ,&nbsp;Lu Feng ,&nbsp;Wenhui Hu ,&nbsp;Yinuo Fan ,&nbsp;Sien Lin ,&nbsp;Gang Li","doi":"10.1016/j.jot.2024.12.004","DOIUrl":"10.1016/j.jot.2024.12.004","url":null,"abstract":"<div><div>Last decade has witnessed increasing evidence which highlights the roles of immune cells in bone regeneration. Numerous immune cell types, including macrophages, T cells, and neutrophils are involved in fracture healing by orchestrating a series of events that modulate bone formation and remodeling. In this review, the role of T cell immunity in fracture healing has been summarized, and the modulatory effects of T cell immunity in inflammation, bone formation and remodeling have been highlighted. The review also summarizes the specific roles of different T cell subsets, including CD4⁺ T cells, CD8⁺ T cells, regulatory T cells, T helper 17 cells, and γδ T cells in modulating fracture healing. The current therapeutics targeting T cell immunity to enhance fracture healing have also been reviewed, aiming to provide insights from a translational standpoint. Overall, this work discusses recent advances and challenges in the interdisciplinary research field of T cell related osteoimmunology and its implications in fracture healing.</div></div><div><h3>The translational potential of this article</h3><div>Delayed unions or non-unions of bone fractures remain a challenge in clinical practice. Developing a deep understanding of the roles of immune cells, including T cells, in fracture healing will facilitate the advancement of novel therapeutics of fracture nonunion. This review summarizes the current understanding of different T cell subsets involved in various phases of fracture healing, providing insights for targeting T cells as an alternative strategy to enhance bone regeneration.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 82-93"},"PeriodicalIF":5.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezoelectric biomaterials for providing electrical stimulation in bone tissue engineering: Barium titanate","authors":"Huagui Huang ,&nbsp;Kaizhong Wang ,&nbsp;Xiangyan Liu ,&nbsp;Xin Liu ,&nbsp;Jinzuo Wang ,&nbsp;Moran Suo ,&nbsp;Hui Wang ,&nbsp;Shuang Chen ,&nbsp;Xin Chen ,&nbsp;Zhonghai Li","doi":"10.1016/j.jot.2024.12.011","DOIUrl":"10.1016/j.jot.2024.12.011","url":null,"abstract":"<div><div>With the increasing clinical demand for orthopedic implants, bone tissue engineering based on a variety of bioactive materials has shown promising applications in bone repair. And various physiological cues, such as mechanical, electrical, and magnetic stimulation, can influence cell fate and participate in bone regeneration. Natural bone has a piezoelectric effect due to the non-centrosymmetric nature of collagen, which can aid in cell adhesion, proliferation and differentiation, and bone growth by converting mechanical stimuli into electrical stimuli. Piezoelectric materials have the same piezoelectric effect as human bone, and they are able to deform in response to physiological movement, thus providing electrical stimulation to cells or damaged tissue without the need for an external power source. Among them, Barium titanate (BaTiO₃) is widely used in tumor therapy, tissue engineering, health detection and drug delivery because of its good biocompatibility, low cytotoxicity and good piezoelectric properties. This review describes the piezoelectric effect of natural bone and the characteristics of various types of piezoelectric materials, from the synthesis and physicochemical characteristics of BaTiO₃ and its application in biomedicine. And it highlights the great potential of BaTiO₃ as piezoelectric biomaterials in the field of bone tissue engineering in anticipation of providing new ideas and opportunities for researchers.</div><div><strong>The translational potential of this article</strong>: This review systematically discusses barium titanate, a bioactive material that can mimic the piezoelectric effect of natural bone tissue, which can intervene in the regenerative repair of bone by providing a sustained electrical microenvironment for bone repair scaffolds. This may help to solve the current problem of poor osteogenic properties of bioactive materials by utilizing barium titanate.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 94-107"},"PeriodicalIF":5.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast growth factor receptor 3 mutation promotes HSPB6-mediated cuproptosis in hypochondroplasia by impairing chondrocyte autophagy","authors":"Jing Chen ,&nbsp;Dan He ,&nbsp;Chengrun Yuan ,&nbsp;Na Li ,&nbsp;Baohong Shi ,&nbsp;Conway Niu ,&nbsp;Jiangfei Yang ,&nbsp;Liangkai Zheng ,&nbsp;Lin Che ,&nbsp;Ren Xu","doi":"10.1016/j.jot.2025.01.011","DOIUrl":"10.1016/j.jot.2025.01.011","url":null,"abstract":"<div><h3>Background</h3><div>Hypochondroplasia (HCH) is a prevalent form of dwarfism linked to mutations in the fibroblast growth factor receptor 3 (<em>FGFR3</em>) gene, causing missense alterations. We previous report was the first to identify <em>FGFR3</em>(G382D) gain-of-function variants with a positive family history as a novel cause of HCH. However, the precise contribution of <em>FGFR3</em> to the pathogenesis of HCH remains elusive.</div></div><div><h3>Methods</h3><div>We generated an <em>Fgfr3</em> (V376D) mutation mouse model using CRISPR/Cas9 technology and performed proteomic analyses to investigate the molecular mechanisms and potential therapeutic targets of HCH. Radiography and micro-computed tomography were employed to assess the bone-specific phenotype in <em>Fgfr3</em> <em>(V376D)</em>mutant mice. Immunofluorescence, western blotting, and flow cytometry were used to systematically investigate the underlying mechanisms and therapeutic targets.</div></div><div><h3>Results</h3><div>We observed that <em>Fgfr3</em> (V376D) mutant mice exhibit a bone-specific phenotype, with symmetrically short limb bones, partially resembling the dwarfism phenotype of patients with HCH. We demonstrated that the mutant-activated FGFR3 promotes heat shock protein B 6 (HSPB6)-mediated cuproptosis by inhibiting chondrocyte autophagy both <em>in vivo</em> and <em>in vitro</em>. Additionally, we revealed that <em>FGFR3</em> (G382D) mutation leads to enhanced ERK signaling, increased Drp1-mediated mitochondrial fission, and upregulated cuproptosis-related protein ferredoxin 1 (FDX1). Furthermore, genetic and pharmacological inhibition of the HSPB6-ERK-Drp1-FDX1 pathway partially alleviate the phenotypes of <em>FGFR3</em> mutants.</div></div><div><h3>Conclusions</h3><div>Our study provides the first evidence for the pathogenicity of a gain-of-function mutation in <em>FGFR3</em> (G382D) using mouse and cell models, and it underscores the potential of targeting the HSPB6-ERK-Drp1-FDX1 axis as a novel therapeutic approach for HCH.</div></div><div><h3>Translational potential of this article</h3><div>We first demonstrate that impaired autophagy and enhanced cuproptosis are pivotal in the pathogenesis of HCH. This study not only enlarged the therapeutic potential of targeting cuproptosis for treating <em>FGFR3</em> mutation-related HCH but also provided a novel perspective on the role of the HSPB6-ERK-Drp1-FDX1 signaling pathway in the development of HCH. Consequently, this article provides valuable insights into the mechanisms and treatment strategies for <em>FGFR3</em> mutation-related chondrodysplasia.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 68-81"},"PeriodicalIF":5.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autologous osteoperiosteal transplantation achieves comparable repair effect and superior interface integration to autologous osteochondral transplantation in porcine osteochondral defects","authors":"Shuai Yang ,&nbsp;En Deng ,&nbsp;Linxin Chen ,&nbsp;Yanbin Pi ,&nbsp;Anhong Wang ,&nbsp;Linghui Dai ,&nbsp;Hongjie Huang ,&nbsp;Xiaoning Duan ,&nbsp;Xin Fu ,&nbsp;Jiying Zhang ,&nbsp;Qinwei Guo ,&nbsp;Weili Shi","doi":"10.1016/j.jot.2024.12.005","DOIUrl":"10.1016/j.jot.2024.12.005","url":null,"abstract":"<div><h3>Background</h3><div>Autologous osteochondral transplantation (AOCT) has been established as an effective treatment strategy for osteochondral defects. Additionally, autologous osteoperiosteal transplantation (AOPT) has emerged as a promising alternative with comparable clinical efficacy. However, a notable gap in the literature exists regarding the specific repair process by the periosteal graft. Therefore, the primary objective of the present study was to assess the osteochondral repair efficacy of AOPT using a porcine model and to elucidate the repair process of the periosteal graft.</div></div><div><h3>Hypothesis</h3><div>AOPT would achieve similar repair effect to AOCT and the grafted periosteum would progressively transform into cartilage-like tissue.</div></div><div><h3>Methods</h3><div>Cylindrical osteochondral defects (8.0 mm in diameter and 5.0 mm in depth) were surgically created bilaterally at the center of the medial femoral condyles in 27 Guangxi Bama minipigs. The 54 knees were randomly allocated into three groups: negative control (n = 18), AOCT (n = 18), and AOPT (n = 18). Osteochondral grafts were harvested from non-weightbearing area of the femoral notch, while osteoperiosteal grafts were from the ipsilateral iliac crest. At 2, 4, and 6 months post-surgery, the knees were subjected to macroscopic, radiographic, nanoindentation and histological evaluations.</div></div><div><h3>Results</h3><div>At 2, 4, and 6 months postoperatively, the gross view evaluation using the International Cartilage Repair Society (ICRS) scoring system and the imaging assessment with the magnetic resonance observation of cartilage repair tissue (MOCART) scoring system showed similar results in the AOCT and AOPT groups, both superior to those of the control group. Nanoindentation analysis revealed near-normal biomechanical properties in the repaired cartilage of both AOPT and AOCT groups. Histological evaluation indicated that the quality of repaired tissues in the AOPT group was comparable to that in the AOCT group. Notably, AOPT consistently exhibited superior interface integration compared to AOCT at all time points.</div></div><div><h3>Conclusion</h3><div>Both AOPT and AOCT demonstrate significant efficacy in promoting the repair of osteochondral defects in a porcine model. Despite similar radiographic findings, mechanical performance and histological structure displayed in both grafted groups, AOPT exhibit superior interface integration, which is critical for effective tissue restoration.</div></div><div><h3>The translational potential of this article</h3><div>As a recently developed procedure for treating osteochondral defects, AOPT has shown promising repair effect and is being increasingly adopted in clinical practice. This study presents histological evidence of the progressive transformation of the periosteum graft into cartilage-like tissue and demonstrates its ability to integrate with the surrounding tissue.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"51 ","pages":"Pages 59-67"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}