Journal of Orthopaedic Translation最新文献

{"title":"New developments in osteoporosis, osteoarthritis and soft tissue repair","authors":"Gang Li (Prof)","doi":"10.1016/j.jot.2024.11.002","DOIUrl":"10.1016/j.jot.2024.11.002","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages A1-A2"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903094","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":"Corrigendum to ‘Osteostaticytes: A novel osteoclast subset couples bone resorption and bone formation’[Journal of Orthopaedic Translation 47 (2024) 144–160]","authors":"Zhiyuan Wei , Jian Zhou , Jie Shen , Dong Sun , Tianbao Gao , Qin Liu , Hongri Wu , Xiaohua Wang , Shulin Wang , Shiyu Xiao , Chao Han , Di Yang , Hui Dong , Yuzhang Wu , Yi Zhang , Shuai Xu , Xian Wang , Jie Luo , Qijie Dai , Jun Zhu , Zhao Xie","doi":"10.1016/j.jot.2024.08.018","DOIUrl":"10.1016/j.jot.2024.08.018","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 339-340"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903086","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":"Recent developments in Achilles tendon risk-analyzing rupture factors for enhanced injury prevention and clinical guidance: Current implications of regenerative medicine","authors":"Maria V. Sankova , Narasimha M. Beeraka , Marine V. Oganesyan , Negoriya A. Rizaeva , Aleksey V. Sankov , Olga S. Shelestova , Kirill V. Bulygin , Hemanth Vikram PR , A.N. Barinov , A.K. Khalimova , Y. Padmanabha Reddy , Basappa Basappa , Vladimir N. Nikolenko","doi":"10.1016/j.jot.2024.08.024","DOIUrl":"10.1016/j.jot.2024.08.024","url":null,"abstract":"<div><h3>Background</h3><div>In recent years, many countries have actively implemented programs and strategies to promote physical education and sports. Despite these efforts, the increase in physical activity has been accompanied by a significant rise in muscle and tendon-ligament injuries, with Achilles tendon rupture being the most prevalent, accounting for 47 % of such injuries. This review aims to summarize all significant factors determining the predisposition of the Achilles tendon to rupture, to develop effective personalized prevention measures.</div></div><div><h3>Objective</h3><div>To identify and evaluate the risk factors contributing to Achilles tendon rupture and to develop strategies for personalized prevention.</div></div><div><h3>Methods</h3><div>This review utilized data from several databases, including Elsevier, Global Health, PubMed-NCBI, Embase, Medline, Scopus, ResearchGate, RSCI, Cochrane Library, Google Scholar, eLibrary.ru, and CyberLeninka. Both non-modifiable and modifiable risk factors for Achilles tendon injuries and ruptures were analyzed.</div></div><div><h3>Results</h3><div>The analysis identified several non-modifiable risk factors, such as genetic predisposition, anatomical and functional features of the Achilles tendon, sex, and age. These factors should be considered when selecting sports activities and designing training programs. Modifiable risk factors included imbalanced nutrition, improper exercise regimens, and inadequate monitoring of Achilles tendon conditions in athletes. Early treatment of musculoskeletal injuries, Achilles tendon diseases, foot deformities, and metabolic disorders is crucial. Long-term drug use and its risk assessment were also highlighted as important considerations. Furthermore, recent clinical advancements in both conventional and surgical methods to treat Achilles tendon injuries were described. The efficacy of these therapies in enhancing functional outcomes in individuals with Achilles injuries was compared. Advancements in cell-based and scaffold-based therapies aimed at enhancing cell regeneration and repairing Achilles injuries were also discussed.</div></div><div><h3>Discussion</h3><div>The combination of several established factors significantly increases the risk of Achilles tendon rupture. Addressing these factors through personalized prevention strategies can effectively reduce the incidence of these injuries. Proper nutrition, regular monitoring, timely treatment, and the correction of metabolic disorders are essential components of a comprehensive prevention plan.</div></div><div><h3>Conclusion</h3><div>Early identification of Achilles tendon risk factors allows for the timely development of effective personalized prevention strategies. These measures can contribute significantly to public health preservation by reducing the incidence of Achilles tendon ruptures associated with physical activity and sports. Continued research and clinical advancements in treatment me","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 289-307"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578322","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":"Innovative development of robot reduction system in geriatric pelvic fractures: A single-center case series in Beijing, China","authors":"Chunpeng Zhao ,&nbsp;Honghu Xiao ,&nbsp;Qiyong Cao ,&nbsp;Yufeng Ge ,&nbsp;Yuneng Li ,&nbsp;Yu Wang ,&nbsp;Gang Zhu ,&nbsp;Xinbao Wu","doi":"10.1016/j.jot.2024.08.023","DOIUrl":"10.1016/j.jot.2024.08.023","url":null,"abstract":"<div><div>Displaced fragility fractures of the pelvis (FFP) pose significant challenges in orthopaedic trauma, owing to patient comorbidities, deteriorating bone quality, and surgical complexities. Despite technological advancements, no robotic methods have been documented for displaced FFP management. To address this, we introduced an advanced robot-assisted fracture reduction system, comprising a tracking device, path planning software, and robotic arms. This study evaluated fifteen consecutive patients with displaced FFP (average age 80.4 ± 9.1 years), who underwent robot-assisted reduction and internal fixation (RARIF) between January 2022 and May 2023. All were categorized as Rommens FFP type III, with a median time of 6 days (range 4–11) from injury to surgery. Operative times averaged 165 ± 44 min, with median blood loss of 50 mL. Postoperative radiographs showed all patients achieved excellent or good reductions as per Matta criteria, marking a 100 % success rate. A 6-month follow-up revealed an average modified Majeed score of 81.4, with 85.7 % of patients rated excellent or good. All fractures healed without complications. Leveraging our intelligent system, RARIF proves to be a safe and effective approach for displaced FFP, facilitating postoperative pain alleviation and early mobilization despite compromised health and bone conditions. This approach may revolutionize the management of FFP in an increasingly aging population, signaling a significant shift in therapeutic strategies.</div><div>Translational Potential of this Article: Elderly patients with displaced FFP often present complex surgical challenges due to comorbidities and poor bone quality, complicating reduction procedures and often leading to ineffective fixation. Addressing these challenges, we have developed an innovative robot-assisted fracture reduction system, offering a practical alternative to conventional methods. This system optimizes the applied force and direction during the reduction process, thereby reducing the needs for manual and repetitive attempts. Our report, detailing the successful implementation of this technique in 15 FFP cases, signifies a considerable leap forward in the field of orthopaedic surgery. This technique notably benefits the elderly population, a group traditionally marginalized in receiving care for complex orthopedic conditions.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 283-288"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554142","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":"Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation","authors":"Rongmin Lin ,&nbsp;Hancheng Lin ,&nbsp;Chencheng Zhu ,&nbsp;Jieming Zeng ,&nbsp;Jiahui Hou ,&nbsp;Ting Xu ,&nbsp;Yihui Tan ,&nbsp;Xuyou Zhou ,&nbsp;Yuan Ma ,&nbsp;Mankai Yang ,&nbsp;Kuanhai Wei ,&nbsp;Bin Yu ,&nbsp;Hangtian Wu ,&nbsp;Zhuang Cui","doi":"10.1016/j.jot.2024.09.005","DOIUrl":"10.1016/j.jot.2024.09.005","url":null,"abstract":"<div><h3>Objective</h3><div>Heterotopic ossification (HO) refers to the abnormal development of bone in soft tissue rather than within bone itself. Previous research has shown that sensory nerve prostaglandin E2 receptor 4 (EP4) signaling not only governs pain perception but also influences bone formation. However, the relationship between sensory nerve EP4 and the pathogenesis of HO in the Achilles tendon remains unclear. This study aims to investigate this relationship and the underlying mechanisms.</div></div><div><h3>Methods</h3><div>We generated sensory nerve EP4-specific knockout mice, with the genotype of Avil-CreEP4^fl/fl, was propagated. Transcriptome sequencing and bioinformatics analysis techniques were used to identify the potential molecular pathways involving with sensory nerve EP4. Additionally, a neurectomy mouse model was created by transecting the sciatic nerve transection, to examine the effects and mechanisms of peripheral innervation on HO in vivo. Micro-CT, immunofluorescence (IF), Hematoxylin and Eosin (H&amp;E) Staining, Safranin O-Fast Green staining and western blotting were used to analyze changes in cellular and tissue components.</div></div><div><h3>Results</h3><div>We here observed an increase in sensory nerve EP4 and H-type vessels during the pathogenesis of HO in both human subjects and mice. Proximal neurectomy through sciatic nerve transection or the targeted knockout of EP4 in sensory nerves hindered angiogenesis-dependent bone formation and the development of HO at the traumatic site of the Achilles tendon. Furthermore, we identified the Efnb2 (Ephrin-B2)/Dll4 (Delta-like ligand 4) axis as a potential downstream element influenced by sensory nerve EP4 in the regulation of HO. Notably, administration of an EP4 inhibitor demonstrated the ability to alleviate HO. Based on these findings, sensory nerve EP4 emerges as an innovative and promising approach for managing HO.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that the sensory nerve EP4 promotes ectopic bone formation by modulating angiogenesis-associated osteogenesis during HO.</div></div><div><h3>The translational potential of this article</h3><div>Our results provide a mechanistic rationale for targeting sensory nerve EP4 as a promising candidate for HO therapy.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 325-338"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587282","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":"Corrigendum to ‘YAP maintains cartilage stem/progenitor cell homeostasis in osteoarthritis’[Journal of Orthopaedic Translation 46 (2024) 79–90]","authors":"Lina Zhang ,&nbsp;Xinxing Wang ,&nbsp;Guang Xia ,&nbsp;Junjie Huang ,&nbsp;Zi Wen ,&nbsp;Chi Liang ,&nbsp;Xu Cao ,&nbsp;Yong Zhou ,&nbsp;Song Wu","doi":"10.1016/j.jot.2024.08.021","DOIUrl":"10.1016/j.jot.2024.08.021","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Page 341"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903089","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":"Mesoporous bioactive glass-enhanced MSC-derived exosomes promote bone regeneration and immunomodulation in vitro and in vivo","authors":"Qingde Wa ,&nbsp;Yongxiang Luo ,&nbsp;Yubo Tang ,&nbsp;Jiaxiang Song ,&nbsp;Penghui Zhang ,&nbsp;Xitao Linghu ,&nbsp;Sien Lin ,&nbsp;Gang Li ,&nbsp;Yixiao Wang ,&nbsp;Zhenyu Wen ,&nbsp;Shuai Huang ,&nbsp;Weikang Xu","doi":"10.1016/j.jot.2024.09.009","DOIUrl":"10.1016/j.jot.2024.09.009","url":null,"abstract":"<div><h3>Background</h3><div>Exosomes produced by mesenchymal stem cells (MSCs) have vascular generative properties and are considered new effective candidates for the treatment of bone defects as alternatives to cell therapy. Improving the pro-regenerative function and efficacy of exosomes has been a popular research topic in the field of orthopaedics.</div></div><div><h3>Methods</h3><div>We prepared mesoporous bioactive glass (mBG) microspheres via the template method. The ionic products of mBGs used to treat MSCs were extracted, and the effects of exosomes secreted by MSCs on osteoblast (OB) and macrophage (MP) behaviour and bone defect repair were observed in vivo (Micro-CT, H&amp;E, Masson, and immunofluorescence staining for BMP2, COL1, VEGF, CD31, CD163, and iNOS).</div></div><div><h3>Results</h3><div>The mBG spheres were successfully prepared, and the Exo-mBG were isolated and extracted. Compared with those in the blank and Exo-Con groups, the proliferation and osteogenic differentiation of OBs in the Exo-mBG group were significantly greater. For example, on Day 7, OPN gene expression in the Ctrl-Exo group was 3.97 and 2.83 times greater than that in the blank and Exo-mBG groups, respectively. In a cranial defect rat model, Exo-mBG promoted bone tissue healing and angiogenesis, increased M2 macrophage polarisation and inhibited M1 macrophage polarisation, as verified by micro-CT, H&amp;E staining, Masson staining and immunofluorescence staining. These effects may be due to the combination of a higher silicon concentration and a higher calcium-to-phosphorus ratio in the mBG ionic products.</div></div><div><h3>Conclusion</h3><div>This study provides insights for the application of exosomes in cell-free therapy and a new scientific basis and technical approach for the utilisation of MSC-derived exosomes in bone defect repair.</div></div><div><h3>The translational potential of this article</h3><div>Our study demonstrated that exosomes produced by mBG-stimulated MSCs have excellent in vitro and in vivo bone-enabling and immunomodulatory functions and provides insights into the use of exosomes in clinical cell-free therapies.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 264-282"},"PeriodicalIF":5.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539564","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":"Engineered melatonin-pretreated plasma exosomes repair traumatic spinal cord injury by regulating miR-138-5p/SOX4 axis mediated microglia polarization","authors":"Hao Chen ,&nbsp;Huihui Sun ,&nbsp;Yaqing Yang ,&nbsp;Pingchuan Wang ,&nbsp;Xizhao Chen ,&nbsp;Junxiang Yin ,&nbsp;Aoying Li ,&nbsp;Liang Zhang ,&nbsp;Jun Cai ,&nbsp;Jijun Huang ,&nbsp;Shengfei Zhang ,&nbsp;Zhiqiang Zhang ,&nbsp;Xinmin Feng ,&nbsp;Jian Yin ,&nbsp;Yongxiang Wang ,&nbsp;Wu Xiong ,&nbsp;Bowen Wan","doi":"10.1016/j.jot.2024.09.007","DOIUrl":"10.1016/j.jot.2024.09.007","url":null,"abstract":"<div><h3>Background</h3><div>Neuroinflammation plays a crucial role in the repair of spinal cord injury (SCI), with microglia, pivotal in neuroinflammation, driving either degeneration or recovery in this pathological process. Recently, plasma-derived exosomes (denoted Exos) have presented a high capacity for promoting functional recovery of SCI through the anti-inflammatory effects, and pretreated exosomes are associated with better outcomes. Thus, we aimed to explore whether melatonin-pretreated plasma-derived exosomes (denoted MExo) could exert superior effects on SCI, and attempted to elucidate the potential mechanisms.</div></div><div><h3>Methods</h3><div>Electron microscopy, nanoparticle tracking analysis, and western blot were applied to delineate the distinctions between Exos and MExos. To assess their therapeutic potentials, we established a contusion SCI rat model, complemented by a battery of in vitro experiments comparing both groups. Subsequently, a miRNA microarray analysis was conducted, followed by a series of rescue experiments to elucidate the specific role of miRNAs in MExos. To further delve into the molecular mechanisms involved, we employed western blot analysis and the luciferase reporter gene assay.</div></div><div><h3>Results</h3><div>Melatonin promoted the release of exosome from plasma, concurrently amplifying their anti-inflammatory properties. Furthermore, it was discerned that MExos facilitated a transition in microglia polarization from M1 to M2 phenotype, a phenomenon more pronounced than that observed with Exos. In an endeavor to elucidate this variance, we scrutinized miRNAs exhibiting elevated expression levels in MExos, pinpointing miR-138-5p as a pivotal element in this dynamic. Following this, an in-depth investigation into the role of miR-138-5p was undertaken, which uncovered its efficacy in driving phenotypic alterations within microglia. The analysis of downstream genes targeted by miR-138-5p revealed that it exerted a negative regulatory influence on SOX4, which was found to obstruct the generation of M2-type microglia and the secretion of anti-inflammatory cytokines, thereby partially elucidating the mechanism behind miR-138-5p′s regulation of microglia polarization.</div></div><div><h3>Conclusions</h3><div>We innovatively observed that melatonin enhanced the anti-inflammatory function of Exos, which further decreased the expression of SOX4 by delivering miR-138-5p. This inhibition promoted the conversion of M1 microglia to M2 microglia, thus offering a viable option for the treatment of SCI.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights that melatonin enhances the anti-inflammatory function of Exos through delivery of miR-138-5p. Activation of miR-138-5p/SOX4 axis by engineered melatonin-pretreated plasma exosomes may be a potential target for SCI treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 230-245"},"PeriodicalIF":5.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526265","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":"Engineering natural DNA matrices with halloysite nanotubes to fabricate injectable therapeutic hydrogels for bone regeneration","authors":"Yali Miao ,&nbsp;Teliang Lu ,&nbsp;Shangbin Cui ,&nbsp;Ziyang Xu ,&nbsp;Xiao Liu ,&nbsp;Yu Zhang","doi":"10.1016/j.jot.2024.09.010","DOIUrl":"10.1016/j.jot.2024.09.010","url":null,"abstract":"<div><h3>Background</h3><div>Injectable hydrogels are widely used in drug delivery and the repair of irregular tissue defects due to their advantages such as convenient and minimally invasive operation. Although the existing injectable hydrogels have excellent biocompatibility and osteoconduction, they still face clinical challenges such as low osteogenic activity. The key requirements for improved injectable hydrogels as repair materials for non-load bearing bone defects are optimal handling properties, the ability to fill irregular defects and provide osteoinductive stimulation.</div></div><div><h3>Methods</h3><div>We developed an approach to construct injectable hydrogels through a two-step gelation process. In the first step of gelation, the denaturation and rehybridization mechanism of natural biopolymer DNA was utilized to form interconnected structure through hydrogen bonding between complementary base pairs between the DNA strands. In the second step of gelation, the introduction of halloysite nanotubes (HNTs) loaded with osteogenic model drug dexamethasone (Dex) provided additional crosslinking sites through non-covalent interactions with the DNA backbone, including electrostatic interaction and hydrogen bonding interaction.</div></div><div><h3>Results</h3><div>The DNA-based nanocomposite hydrogel material developed in our work can be used as an injectable filling material for the repair of non-load bearing bone defect and can be loaded with osteogenic model drug dexamethasone (Dex) for improved osteoinductivity, promoting new bone regeneration <em>in vivo</em>.</div></div><div><h3>Translational potential of this article</h3><div>This article highlights the potential of using nanocomposite hydrogels to repair non-load bearing bone defects, which are common injuries in the clinic. This study provides a deeper understanding of how to optimize the properties of hydrogels to regulate cell differentiation and tissue formation.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 218-229"},"PeriodicalIF":5.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526264","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":"IHH–GLI-1–HIF-2α signalling influences hypertrophic chondrocytes to exacerbate osteoarthritis progression","authors":"Chengming Zhang ,&nbsp;Ruipeng Zhao ,&nbsp;Zhengquan Dong ,&nbsp;Yang Liu ,&nbsp;Mengrou Liu ,&nbsp;Haoqian Li ,&nbsp;Yukun Yin ,&nbsp;Xianda Che ,&nbsp;Gaige Wu ,&nbsp;li Guo ,&nbsp;Pengcui Li ,&nbsp;Xiaochun Wei ,&nbsp;Ziquan Yang","doi":"10.1016/j.jot.2024.09.008","DOIUrl":"10.1016/j.jot.2024.09.008","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Chondrocyte hypertrophy is a potential target for osteoarthritis (OA) treatment, with Indian hedgehog (IHH), glioma-associated oncogene homolog (GLI), and hypoxia-inducible factor-2α (HIF-2α) being closely associated with chondrocyte hypertrophy during OA progression. Whereas IHH can modulate chondrocyte hypertrophy, interference with IHH signalling has not achieved the anticipated therapeutic effects and poses safety concerns, necessitating further clarification of the specific mechanisms by which IHH affects articular cartilage degeneration. Inhibition of the HIF-2α overexpression in cartilage slows the progression of early OA, but the mechanisms underlying HIF-2α accumulation in OA cartilage remain unclear. The aim of this study was to determine the function of Ihh, as well as its downstream factors, in chondrocytes, based on an early osteoarthritis (OA) mouse model and in vitro chondrocyte model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Investigated the expression levels and locations of IHH–GLI-1 pathway in normal and early degenerated human cartilage, comparing them with HIF-2α and its downstream factors. RT-qPCR, Western blotting, Crystal violet staining, and EdU assays were used to evaluate the pecific regulatory mechanisms of the IHH–GLI-1–HIF-2α signalling axis in normal chondrocytes and in chondrocytes under inflammatory conditions. Validated the impact of IHH on early cartilage degeneration and the relationship between the IHH-GLI-1 pathway and the expression levels and expression locations of HIF-2α and its downstream factors in Col2a1-Cre&lt;sup&gt;ERT2&lt;/sup&gt;;Ihh&lt;sup&gt;fl/fl&lt;/sup&gt; mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In early-stage degenerative joint cartilage, the GLI-1 pathway in hypertrophic chondrocytes exhibited similar changes in location and levels to HIF-2α and its downstream factor vascular endothelial growth factor (VEGF). In vitro, IHH–GLI-1–HIF-2α signalling activation in chondrocytes under physiological hypoxic conditions inhibited chondrocyte proliferation. In chondrocytes stimulated by inflammatory environments, IHH inhibited the degradation of HIF-2α via the GLI-1 pathway, thereby promoting HIF-2α protein expression. Elevated HIF-2α expression further enhanced intracellular IHH–GLI-1 levels, generating a positive feedback loop to collectively regulate the expression of downstream hypertrophic factors and matrix-degradation factors. &lt;em&gt;In vivo&lt;/em&gt;, conditional &lt;em&gt;Ihh&lt;/em&gt; knockout in mouse chondrocytes downregulated Hif-2α protein expression in early degenerative cartilage tissue and affected the expression of downstream Vegf and hypertrophic factors.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;During OA progression, the IHH–GLI-1–HIF-2α axis mainly operates within hypertrophic chondrocytes, exacerbating cartilage degeneration by regulating hypertrophic chondrocyte functions, cartilage matrix degradation, and microvascular invasion.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 207-217"},"PeriodicalIF":5.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526263","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}