Journal of Orthopaedic Translation最新文献

{"title":"Zhuangyao Jianshen Wan ameliorates senile osteoporosis in SAMP6 mice through Modulation of the GCN5L1-mediated PI3K/Akt/wnt signaling pathway","authors":"Shaoyong Ma , Jian Lin , Meng Yang , JiaJia Wang , Lujiao Lu , Ying Liang , Yan Yang , Yanzhi Liu , Dongtao Wang , Yajun Yang","doi":"10.1016/j.jot.2024.08.009","DOIUrl":"10.1016/j.jot.2024.08.009","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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&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.</div></div><div><h3>Results</h3><div>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 , 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":"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}

{"title":"Role of oxidative stress in mitochondrial dysfunction and their implications in intervertebral disc degeneration: Mechanisms and therapeutic strategies","authors":"Hao Zhou ,&nbsp;Chenyu Wu ,&nbsp;Yuxin Jin ,&nbsp;Ouqiang Wu ,&nbsp;Linjie Chen ,&nbsp;Zhenyu Guo ,&nbsp;Xinzhou Wang ,&nbsp;Qizhu Chen ,&nbsp;Kenny Yat Hong Kwan ,&nbsp;Yan Michael Li ,&nbsp;Dongdong Xia ,&nbsp;Tao Chen ,&nbsp;Aimin Wu","doi":"10.1016/j.jot.2024.08.016","DOIUrl":"10.1016/j.jot.2024.08.016","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Intervertebral disc degeneration (IVDD) is widely recognized as one of the leading causes of low back pain. Intervertebral disc cells are the main components of the intervertebral disc (IVD), and their functions include synthesizing and secreting collagen and proteoglycans to maintain the structural and functional stability of the IVD. In addition, IVD cells are involved in several physiological processes. They help maintain nutrient metabolism balance in the IVD. They also have antioxidant and anti-inflammatory effects. Because of these roles, IVD cells are crucial in IVDD. When IVD cells are subjected to oxidative stress, mitochondria may become damaged, affecting normal cell function and accelerating degenerative changes. Mitochondria are the energy source of the cell and regulate important intracellular processes. As a key site for redox reactions, excessive oxidative stress and reactive oxygen species can damage mitochondria, leading to inflammation, DNA damage, and apoptosis, thus accelerating disc degeneration.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Aim of review&lt;/h3&gt;&lt;div&gt;Describes the core knowledge of IVDD and oxidative stress. Comprehensively examines the complex relationship and potential mechanistic pathways between oxidative stress, mitochondrial dysfunction and IVDD. Highlights potential therapeutic targets and frontier therapeutic concepts. Draws researchers' attention and discussion on the future research of all three.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Key scientific concepts of review&lt;/h3&gt;&lt;div&gt;Origin, development and consequences of IVDD, molecular mechanisms of oxidative stress acting on mitochondria, mechanisms of oxidative stress damage to IVD cells, therapeutic potential of targeting mitochondria to alleviate oxidative stress in IVDD.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;Targeted therapeutic strategies for oxidative stress and mitochondrial dysfunction are particularly critical in the treatment of IVDD. Using antioxidants and specific mitochondrial therapeutic agents can help reduce symptoms and pain. This approach is expected to significantly improve the quality of life for patients. Individualized therapeutic approaches, on the other hand, are based on an in-depth assessment of the patient's degree of oxidative stress and mitochondrial functional status to develop a targeted treatment plan for more precise and effective IVDD management. Additionally, we suggest preventive measures like customized lifestyle changes and medications. These are based on understanding how IVDD develops. The aim is to slow down the disease and reduce the chances of it coming back. Actively promoting clinical trials and evaluating the safety and efficacy of new therapies helps translate cutting-edge treatment concepts into clinical practice. These measures not only improve patient outcomes and quality of life but also reduce the consumption of healthcare resources and the socio-economic burden, thus having a positiv","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 181-206"},"PeriodicalIF":5.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442735","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":"A biodegradable magnesium phosphate cement incorporating chitosan and rhBMP-2 designed for bone defect repair","authors":"Peng He ,&nbsp;Yanbin Zhao ,&nbsp;Bin Wang ,&nbsp;Guoyin Liu ,&nbsp;Lei Zhang ,&nbsp;Mei Li ,&nbsp;Bin Xu ,&nbsp;Weihua Cai ,&nbsp;Chenglin Chu ,&nbsp;Yu Cong","doi":"10.1016/j.jot.2024.08.004","DOIUrl":"10.1016/j.jot.2024.08.004","url":null,"abstract":"<div><h3>Background</h3><div>The repair of bone defects has always been a significant challenge in clinical medicine. To address this challenge, doctors often utilize autologous bone grafts, allogeneic bone grafts and artificial bone substitutes. However, the former two methods may result in additional trauma and complications, while allogeneic bone grafts carry the risks of immune rejection and disease transmission. Magnesium phosphate cement (MPC), as a artificial bone substitutes, has been a potential biomaterial for repairing bone defects, but its clinical application is limited by insufficient mechanical strength and poor osteoinductive activity.</div></div><div><h3>Methods</h3><div>In this study, the cement liquid phase base on rhBMP-2 and chitosan solution into MPC were obtained and investigated. After mixing with a cement liquid, the structural and phase composition, morphology, chemical structure, setting time, compressive strength, degradation behavior, solubility, and cellular responses and bone regeneration in response to CHI-rhBMP2 MPC were investigated in vitro and in vivo.</div></div><div><h3>Results</h3><div>After the chemical component modification, CHI-rhBMP2 MPC possessed controllable degradation rate, moderate setting time, appropriate cuing temperature, good injectability, and improved initial strength. In vitro tests showed that the CHIrhBMP2 MPC could promote cell proliferation and adhesion, as well as that contribute to osteoblast differentiation and mineralization. In addition, cement materials were implanted into the rabbit femoral condyles for in vivo osseointegration evaluation. The results displayed that more new bone grew around CHI-rhBMP2 MPC, verifying improved osseointegration capacity. Transcriptome analysis revealed that focal adhesion, Forkhead box O（FoxO） signaling pathway and P13K/AKT signaling pathway were may involved in CHI-rhBMP2 MPC induced new bone formation.</div></div><div><h3>Conclusion</h3><div>This work provides a new strategy for the rational design of potential bone repair candidate materials.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 167-180"},"PeriodicalIF":5.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433287","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}