Journal of Orthopaedic Translation最新文献

{"title":"OGT mediated HDAC5 O-GlcNAcylation promotes osteogenesis by regulating the homeostasis of epigenetic modifications and proteolysis","authors":"Yu Du ,&nbsp;Xiang Gao ,&nbsp;Jianqiang Chen ,&nbsp;Xinxin Chen ,&nbsp;Hang Liu ,&nbsp;Wenge He ,&nbsp;Lu Liu ,&nbsp;Yue Jiang ,&nbsp;Baicheng He ,&nbsp;Zhongliang Deng ,&nbsp;Chao Liang ,&nbsp;Fengjin Guo","doi":"10.1016/j.jot.2024.10.004","DOIUrl":"10.1016/j.jot.2024.10.004","url":null,"abstract":"<div><h3>Background</h3><div>O-GlcNAc transferase (OGT) is responsible for attaching O-linked N-acetylglucosamine (O-GlcNAc) to proteins, regulating diverse cellular processes ranging from transcription and translation to signaling and metabolism. This study focuses on the role and mechanisms of OGT in osteogenesis.</div></div><div><h3>Materials and methods</h3><div>We found that OGT is downregulated in osteoporosis by bioinformatics analysis, determined its role in osteogenic differentiation by using OGT inhibitors (or OGA inhibitors) as well as conditional knockout OGT mice in <em>vitro</em> and in <em>vivo</em>, and explored and specific mechanisms by quantitative proteomic analysis and RNA-seq, qRT-PCR, western blotting, immunofluorescence, H&amp;E, ALP, ARS, Masson staining, IHC, micro CT, etc.</div></div><div><h3>Results</h3><div>we revealed that OGT positively influenced osteogenesis and osteoblast differentiation in <em>vitro</em> as well as ovariectomy (OVX) mice in <em>vivo</em>. Consistently, mice with conditionally depleted OGT exhibited a reduction in bone mass, while O-GlcNAcylation enhancer could partially recover bone mass in ovariectomy (OVX) mice. Mechanistically, quantitative proteomic analysis and high-throughput RNAseq further reveals that HDAC5 is one of the endogenous O-GlcNAcylation substrates, and O-GlcNAcylation of HDAC5 on Thr934 promotes its translocation to lysosomes and subsequent degradation, thus, elevating the O-GlcNAcylation level of HDAC5 leads to its cytoplasmic cleavage, consequently diminished its nuclear entry and enhanced DNA transcription. The OGT-mediated O-GlcNAcylation of HDAC5 modulates the balance between its cytoplasmic proteolysis and nuclear entry, thereby impacting the Notch signaling pathway and DNA epigenetic modifications then playing a role in osteogenesis.</div></div><div><h3>Conclusion</h3><div>OGT is a regulator that promotes osteoblast differentiation and bone regeneration. Additionally, it highlights the critical function of HDAC5 O-GlcNAcylation in controlling epigenetics. This study offers fresh perspectives on osteogenesis and O-GlcNAcylation, proposing that the OGT-mediated O-GlcNAcylation of HDAC5 could be a promising target for osteoporosis treatment.</div></div><div><h3>The translational potential of this article</h3><div>On one side, OGT might potentially be used as a new biomarker for clinical diagnosis of osteoporosis (OP) in the future. On the other side, small molecule inhibitors of HDAC5, a glycosylation substrate of OGT, or OGT agonists such as silymarin, could all potentially serve as therapeutic targets for the prevention or treatment of OP in the future.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"Pages 14-29"},"PeriodicalIF":5.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142703343","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":"Paeonol inhibits ACSL4 to protect chondrocytes from ferroptosis and ameliorates osteoarthritis progression","authors":"Siyang Cao ,&nbsp;Yihao Wei ,&nbsp;Ao Xiong ,&nbsp;Yaohang Yue ,&nbsp;Jun Yang ,&nbsp;Deli Wang ,&nbsp;Xiyu Liu ,&nbsp;Hui Zeng ,&nbsp;Dongquan Shi ,&nbsp;Ye Li","doi":"10.1016/j.jot.2024.10.005","DOIUrl":"10.1016/j.jot.2024.10.005","url":null,"abstract":"<div><h3>Background</h3><div>Discovering an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein that triggers cell injury via ferroptosis, presents potential to minimize cellular damage. This study investigates paeonol (PAE), a traditional Chinese herbal medicine, as an ACSL4 inhibitor to prevent chondrocyte ferroptosis and protect against osteoarthritis (OA).</div></div><div><h3>Methods</h3><div>We conducted <em>in vitro</em> experiments using mouse chondrocytes treated with PAE to mitigate ferroptosis induced by Interleukin-1 Beta (IL-1β) or ferric ammonium citrate (FAC), examining intracellular ferroptotic indicators, cartilage catabolic markers, and ferroptosis regulatory proteins. A mouse OA model was created via destabilized medial meniscus (DMM), followed by intra-articular PAE injections. After 8 weeks, micro-computed tomography and histological assessments evaluated PAE's protective and anti-ferroptotic effects in the OA model.</div></div><div><h3>Results</h3><div><em>In vitro</em> results showed PAE significantly reduced IL-1β/FAC-induced damage by targeting ACSL4, including cell apoptosis, inflammatory responses, extracellular matrix degradation, and ferroptotic markers (oxidative stress, lipid peroxidation, and iron buildup). It also restored the expression of ferroptotic suppressors and mitigated mitochondrial damage. Additionally, PAE increased cartilage anabolic marker expression while reducing cartilage catabolic marker expression. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability analysis verified the binding interaction between PAE and ACSL4. Furthermore, the role of PAE in chondrocytes was further verified through ACSL4 knockdown and overexpression. <em>In vivo</em>, mice with OA showed increased cartilage degradation and ferroptosis, while intra-articular PAE injection alleviated these pathological changes.</div></div><div><h3>Conclusion</h3><div>PAE significantly protects chondrocytes from ferroptosis induced by IL-1β/FAC in primary mouse chondrocytes and DMM surgery-induced OA mice through ACSL4 inhibition.</div></div><div><h3>The translational potential of this article</h3><div>These findings highlight the potential of targeting ACSL4 in chondrocytes as a treatment strategy for OA, positioning PAE as a promising drug candidate.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"Pages 1-13"},"PeriodicalIF":5.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142703790","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":"Zhuangyao Jianshen Wan ameliorates senile osteoporosis in SAMP6 mice through Modulation of the GCN5L1-mediated PI3K/Akt/wnt signaling pathway","authors":"Shaoyong Ma ,&nbsp;Jian Lin ,&nbsp;Meng Yang ,&nbsp;JiaJia Wang ,&nbsp;Lujiao Lu ,&nbsp;Ying Liang ,&nbsp;Yan Yang ,&nbsp;Yanzhi Liu ,&nbsp;Dongtao Wang ,&nbsp;Yajun Yang","doi":"10.1016/j.jot.2024.08.009","DOIUrl":"10.1016/j.jot.2024.08.009","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Senile osteoporosis (SOP) is a systemic bone disease characterized by increased susceptibility to fractures. However, there is currently no effective treatment for SOP. The Zhuangyao Jianshen Wan (ZYJSW) pill is traditionally believed to possess kidney-nourishing and bone-strengthening effects, demonstrating efficacy in treating fractures. Despite this, its effectiveness and mechanism in SOP remain unclear. This study aims to investigate the therapeutic potential of ZYJSW in treating SOP in senescence accelerated mouse prone 6 (SAMP6, P6) mice, and elucidate the underlying mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Four-month-old SAMP6 mice were categorized into six groups: the model group (SAMP6), low, medium, and high-dose ZYJSW treatment groups, calcitriol treatment (positive control 1) group, and metformin treatment (positive control 2) group. Gastric administration was carried out for 15 weeks, and a normal control group comprising four-month-old Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice. Changes in body weight, liver and kidney function, bone protective effects, and muscle quality were evaluated using various assays, including H&amp;E staining, Goldner staining, bone tissue morphology analysis, Micro-CT imaging, and biomechanical testing. Qualitative analysis and quality control of ZYJSW were performed via LC-MS/MS analysis. To explore mechanisms, network pharmacology and proteomics were employed, and the identified proteins were validated by Western blotting.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Oral administration of ZYJSW to P6 mice exerted preventive efficacy against osteopenia, impaired bone microstructure, and poor bone and muscle quality. ZYJSW attenuated the imbalance in bone metabolism by promoting bone formation, as evidenced by the upregulation of key factors such as Runt-related transcription factor 2 (RUNX2), Bone Morphogenetic Protein (BMP2), Osteoprotegerin (OPG) and Osteocalcin (OCN), while simultaneously inhibiting bone resorption through the downregulation of TNF receptor associated factor 6 (TRAF6), Tartrate resistant acid phosphatase (TRAP), Receptor activator for nuclear factor-κB ligand (RANKL) and Cathepsin K (CTSK). Additionally, ZYJSW enhanced muscle structure and function by counteracting the elevation of Ubiquitin (Ub), Muscle RING-finger protein-1 (Murf-1), F-Box Protein 32 (FBOX32), and Myogenin (Myog). Network pharmacology predictions, proteomics analysis corroborated by published literature demonstrated the role of ZYJSW involving in safeguarding mitochondrial biogenesis. This was achieved by suppressing GCN5L1 expression, contributing to the heightened expression of TFAM, PGC-1α, and nuclear respiratory factor-1 (NRF-1) proteins. ZYJSW also positively modulated Wnt signaling pathways responsible for bone formation, due to regulating expressions of key components like β-catenin, GSK-3β, and LRP5. In addition, ZYJSW causes the downregulation of the PI3K/Akt pathway","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 308-324"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587281","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 ,&nbsp;Narasimha M. Beeraka ,&nbsp;Marine V. Oganesyan ,&nbsp;Negoriya A. Rizaeva ,&nbsp;Aleksey V. Sankov ,&nbsp;Olga S. Shelestova ,&nbsp;Kirill V. Bulygin ,&nbsp;Hemanth Vikram PR ,&nbsp;A.N. Barinov ,&nbsp;A.K. Khalimova ,&nbsp;Y. Padmanabha Reddy ,&nbsp;Basappa Basappa ,&nbsp;Vladimir N. Nikolenko","doi":"10.1016/j.jot.2024.08.024","DOIUrl":"10.1016/j.jot.2024.08.024","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;To identify and evaluate the risk factors contributing to Achilles tendon rupture and to develop strategies for personalized prevention.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Discussion&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;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":"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}