Journal of Orthopaedic Translation最新文献

{"title":"Bioabsorbable magnesium-based bulk metallic glass composite (BMGC) for improved medial opening wedge high tibial osteotomy in knee osteoarthritis.","authors":"Kuan-Hao Chen, Pei-Chun Wong, Lekha Rethi, Wei-Ru Wang, Chieh-Ying Chen, Pei-Hua Tsai, Jason Shian-Ching Jang, Chun-Li Lin, Chih-Hwa Chen, Andrew E-Y Chuang","doi":"10.1016/j.jot.2024.10.001","DOIUrl":"10.1016/j.jot.2024.10.001","url":null,"abstract":"<p><strong>Background and objective: </strong>Osteoarthritis is a widespread and debilitating condition, particularly affecting the medial compartment of knee joint due to varus knee deformities. Medial opening wedge high tibial osteotomy (MOWHTO) has emerged as an effective treatment, but it comes with challenges like fractures, correction loss, and nonunion, leading to unsatisfactory results in up to 26 % of patients. In response, our study explores the potential of a bioabsorbable magnesium-based bulk metallic glass composite (Mg₆₇Zn₂₈Ca₅ BMGC) enriched with molybdenum particles as an innovative solution for MOWHTO.</p><p><strong>Methods: </strong>Our comprehensive study includes composite fabrication, mechanical property evaluations, in vitro degradation tests, cell viability assessments, cell migration assays, calcium deposition analyses, and osteoblast differentiation investigations. In vivo experiments were commenced for assessing biological effects and bone growth of the Mg₆₇Zn₂₈Ca₅ BMGC in an animal model. Finite element analysis was utilized for assessing the mechanical impact of the composite wedge in human MOWHTO.</p><p><strong>Results: </strong>The findings indicate that the Mg₆₇Zn₂₈Ca₅ BMGC closely matches human cortical bone's mechanical properties, with controlled degradation and superior cellular responses. In vivo experiments reveal progressive degradation and bone integration. Finite element analysis confirms the composite's mechanical effectiveness in MOWHTO.</p><p><strong>Conclusion: </strong>In conclusion, our research introduces an innovative Mg₆₇Zn₂₈Ca₅ BMGC enriched with molybdenum particles, showing promising mechanical and degradation characteristics. It has the potential to improve MOWHTO surgeries by matching cortical bone properties, controlled degradation, and promoting beneficial ion release for bone health. Successful tissue integration suggests suitability for high tibial osteotomy surgeries, offering hope for better outcomes in knee osteoarthritis patients.</p><p><strong>The translational potential of this article: </strong>This article focuses on meeting the advantages of a novel magnesium-based BMGC with the clinical unmet need of MOWHTO surgeries. If properly developed, the results of this article have significant potential of translation to other temporary orthopedic implants under load-bearing conditions.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"97-110"},"PeriodicalIF":5.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047031","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":"Single-cell transcriptomics identifies the common perturbations of monocyte/macrophage lineage cells in inflammaging of bone marrow.","authors":"Peng Liao, Sihan Tong, Lin Du, Jiong Mei, Bingqi Wang, Yafei Lu, Meng Yao, Changqing Zhang, Delin Liu, Zhigang Zhong, Fang Ye, Junjie Gao","doi":"10.1016/j.jot.2024.09.013","DOIUrl":"10.1016/j.jot.2024.09.013","url":null,"abstract":"<p><strong>Background: </strong>Bone marrow inflammaging is a low-grade chronic inflammation that induces bone marrow aging. Multiple age-related and inflammatory diseases involve bone marrow inflammaging. Whether common pathological pathways exist in bone marrow inflammaging remains unclear.</p><p><strong>Methods: </strong>We collected bone marrow from telomerase-deficient mice (telomerase RNA component, TERC^ko/ko), 5 × FAD mice and <i>Dmp1</i> ^<i>Cre</i> <i>-DTA</i> ^<i>ki/wt</i> mice and High-fat diet-fed mice (HFD), and lumbar 5 nerve compression mice. We performed scRNA-Seq analysis on bone marrow obtained from these mouse models to investigate the potential shared pathway of bone marrow inflammation.</p><p><strong>Results: </strong>We identified the monocyte/macrophage lineage was activated via the App-Cd74 axis in multiple aging and inflammatory mouse models. Increased expression of CD38 and Ly6a, and decreased expression of Col1a and Lif in macrophages serve as shared changes in different mouse models. The activated macrophages, interacting with other cells, control the expansion of B cells via the CD52-Siglec-G axis. The Ccl6-Ccr2 and Ccl9-Ccr1 ligand-receptor pairs, along with Fn1 and C3-related pathways in macrophages, were associated with immune cell activation and the recruitment of lymphocytes. Interactions with mesenchymal cells were enriched for integrins (Itga4), Fn1, and adhesion molecules (Vcam1).</p><p><strong>Conclusion: </strong>Our study demonstrates that monocyte/macrophage lineage stimulation is a key event in bone marrow inflammaging. We identified common differentially expressed genes and activated pathways in this lineage, suggesting potential targets for future interventions.</p><p><strong>The translational potential of this article: </strong>Our study revealed shared genes and ligand-receptor pairs in the activated monocyte/macrophage lineage within inflammaging bone marrow. These findings offer potential therapeutic targets for cell-specific anti-inflammatory treatments.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"85-96"},"PeriodicalIF":5.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047035","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":"Harnessing the potential of hyaluronic acid methacrylate (HAMA) hydrogel for clinical applications in orthopaedic diseases.","authors":"Junliang Lu, Zhifei Gao, Wei He, Yao Lu","doi":"10.1016/j.jot.2024.11.004","DOIUrl":"10.1016/j.jot.2024.11.004","url":null,"abstract":"<p><p>The treatment of orthopaedic diseases, such as fractures and osteoarthritis, remains a significant challenge due to the complex requirements for mechanical strength and tissue repair. Hydrogels based on hyaluronic acid methacrylate (HAMA) show promise as tissue engineering materials for these conditions. Hyaluronic acid (HA) is a natural component of the extracellular matrix, known for its good compatibility. The mechanical strength of HAMA-based hydrogels can be adjusted through crosslinking and by combining them with other materials. This review provides an overview of recent research on HAMA-based hydrogels for tissue engineering applications in orthopaedic diseases. First, we summarize the techniques for the preparation and characterization of HAMA hydrogels. Next, we offer a detailed review of the use of HAMA-based hydrogels in treating conditions such as cartilage injuries, bone defects, and meniscus injuries. Additionally, we discuss the applications of HAMA-based hydrogels in other diseases related to orthopaedics. Finally, we point out the challenges and propose future directions for the clinical translation of HAMA-based hydrogels.</p><p><strong>Translational potential statement: </strong>HAMA-based hydrogels show strong translational potential in orthopaedics due to their biocompatibility, adjustable mechanical properties, and regenerative capabilities. With ongoing research, these hydrogels are well-positioned for clinical applications, particularly in cartilage repair, meniscus injuries, and osteoarthritis treatment.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"111-128"},"PeriodicalIF":5.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065586","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":"Innovating intervertebral disc degeneration therapy: Harnessing the power of extracellular vesicles.","authors":"Shanfeng Chen, Yiming Dou, Yiming Zhang, Xun Sun, Xinyu Liu, Qiang Yang","doi":"10.1016/j.jot.2024.09.014","DOIUrl":"10.1016/j.jot.2024.09.014","url":null,"abstract":"<p><p>Intervertebral disc degeneration is the leading cause of low back pain, imposing significant burdens on patients, societies, and economies. Advancements in regenerative medicine have spotlighted extracellular vesicles as promising nanoparticles for intervertebral disc degeneration treatment. Extracellular vesicles retain the potential of cell therapy and serve as carriers to deliver their cargo to target cells, thereby regulating cell activity. This review summarizes the biogenesis and molecular composition of extracellular vesicles and explores their therapeutic roles in intervertebral disc degeneration treatment through various mechanisms. These mechanisms include mitigating cell loss and senescence, delaying extracellular matrix degeneration, and modulating the inflammatory microenvironment. Additionally, it highlights recent efforts in engineering extracellular vesicles to enhance their targeting and therapeutic efficacy. The integration of extracellular vesicle-based acellular therapy is anticipated to drive significant advancements in disc regenerative medicine.</p><p><strong>The translational potential of this article: </strong>Existing clinical treatment strategies often fail to effectively address the challenges associated with regenerating degenerated intervertebral discs. As a new regenerative medicine strategy, the extracellular vesicle strategy avoids the risks associated with cell transplantation and shows great promise in treating intervertebral disc degeneration by carrying therapeutic cargo. This review comprehensively examines the latest research, underlying mechanisms, and therapeutic potential of extracellular vesicles, offering a promising new strategy for intervertebral disc degeneration treatment.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"44-55"},"PeriodicalIF":5.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047032","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":"The role of metabolites in the progression of osteoarthritis: Mechanisms and advances in therapy.","authors":"Xiaofeng Liu, Yongqiang Zheng, Hao Li, Yiyang Ma, Ruomu Cao, Zhikai Zheng, Yuchen Tian, Lin Du, Jinshan Zhang, Changqing Zhang, Junjie Gao","doi":"10.1016/j.jot.2024.10.003","DOIUrl":"10.1016/j.jot.2024.10.003","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a progressive degenerative disease affected by many factors, and there is currently no effective treatment. In recent years, the latest progress in metabolomics in OA research has revealed several metabolic pathways and new specific metabolites involved in OA. Metabolites play significant roles in the identification and management of OA. This review looks back on the development history of metabolomics and the progress of this technology in OA as well as its potential clinical applications. It summarizes the applications of metabolites in the field of OA and future research directions. This understanding will advance the identification of metabolic treatment goals for OA.</p><p><strong>The translational potential of this article: </strong>The development of metabolomics offers possibilities for the treatment of OA. This article reviews the relationship between metabolites associated with chondrocytes and OA. Selectively altering these three metabolic pathways and their associated metabolites may hold great potential as new focal points for OA treatment.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"56-70"},"PeriodicalIF":5.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047037","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":"Accelerated fracture healing accompanied with traumatic brain injury: A review of clinical studies, animal models and potential mechanisms.","authors":"Zheyu Jin, Ziyi Chen, Tongzhou Liang, Weiyang Liu, Zhengming Shan, Dianhui Tan, Jiechen Chen, Jun Hu, Ling Qin, Jiankun Xu","doi":"10.1016/j.jot.2024.10.008","DOIUrl":"10.1016/j.jot.2024.10.008","url":null,"abstract":"<p><p>The orthopaedic community frequently encounters polytrauma individuals with concomitant traumatic brain injury (TBI) and their fractures demonstrate accelerated fracture union, but the mechanisms remain far from clear. Animal and clinical studies demonstrate robust callus formation at the early healing process and expedited radiographical union. In humans, robust callus formation in TBI occurs independently of fracture fixation methods across multiple fracture sites. Animal studies of TBI replicate clinically relevant enlarged fracture callus as characterized by increased tissue volume and bone volume at the early stages. However, refinement and standardization of the TBI models requires further research. The quest for its underlying mechanisms began with the finding of increased osteogenesis <i>in vitro</i> using the serum and cerebral spinal fluid (CSF) from TBI individuals. This has led to the investigation of myriads of brain-derived factors including humoral factors, cytokines, exosomes, and mi-RNAs. Further, the emerging information of interplay between the skeletal system and central nervous system, the roles of peripheral nerves and their neuropeptides in regulating bone regeneration, offers valuable insights for future research. This review consolidates the findings from both experimental and clinical studies, elucidating the potential mechanisms underlying enhanced fracture healing in concurrent TBI scenarios that may lay down a foundation to develop innovative therapies for fracture healing enhancement and conquer fracture non-union. The translational potential of this article. This review comprehensively summarizes the observations of accelerated fracture healing in the presence of traumatic brain injury from both preclinical and clinical studies. In addition, it also delineates potential cellular and molecular mechanisms. Further detailed investigation into its underlying mechanisms may reveal innovative orthopaedic intervention strategies to improve fracture healing and thus offering promising avenues for future translational applications.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"71-84"},"PeriodicalIF":5.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047030","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":"Sirt1 blocks nucleus pulposus and macrophages crosstalk by inhibiting RelA/Lipocalin 2 axis.","authors":"Yi-Fan Wei, He-Long Zhang, Ling-Zhi Li, You Lv, He Li, Zhi Li, Feng-Lei Yu, Tao Jiang, Tian-You Zhang, Feng Xin, Cheng Ma, Yong-Xin Ren","doi":"10.1016/j.jot.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.jot.2024.11.008","url":null,"abstract":"<p><strong>Background: </strong>Intervertebral disc degeneration (IVDD) stands as a primary pathophysiological driver of low back pain, yet no therapeutic intervention effectively arrests its progression. Evidence shows that certain Sirt1 agonists may confer protective effects on intervertebral discs, but the underlying mechanisms remain unclear. This study aims to delineate the interaction between Sirt1 and the inflammatory microenvironment, offering potential novel avenues for IVDD prevention and treatment.</p><p><strong>Methods: </strong><i>In vitro</i> IL-1β-induced nucleus pulposus cells (NPCs) degenerative model and <i>in vivo</i> a mouse annulus fibrosus needle puncture model in Sirt1 transgenic (Sirt1^TG) and the same litter WT mice were used to investigate the role of Sirt1 in homeostasis and inflammation. Mechanistic insights were obtained through RNA sequencing, co-immunoprecipitation (Co-IP), luciferase assays, and chromatin immunoprecipitation-(ChIP)-PCR. A co-culture system of Raw264.7 and NPCs was employed to assess the involvement of Lipocalin 2.</p><p><strong>Results: </strong>Our study demonstrated reduced Sirt1 expression in degenerating human nucleus pulposus (NP) tissue. Both <i>in vitro</i> and <i>in vivo</i> data revealed that NP-specific overexpression of Sirt1 inhibited extracellular matrix degradation and inflammation. Mechanistically, Sirt1 suppressed the acetylation of RelA/p65 at lysine 310 and phosphorylation at serine 536, with the C-terminus of Sirt1 and the RHD-NLS domain of RelA mediating to their interaction. Furthermore, NPCs-derived Lipocalin 2 was identified as a cytokine involved in macrophage chemotaxis and M1 polarization to exacerbate inflammation.</p><p><strong>Conclusion: </strong>Our work revealed that Sirt1 negatively regulates Lipocalin 2, thereby ameliorating the inflammatory milieu and blocking NPCs and macrophages crosstalk.</p><p><strong>The translational potential of this article: </strong>This study illuminates the crucial role and molecular mechanisms of Sirt1 in regulating the NP microenvironment. These insights shed light on strategies for the prevention and treatment of IVDD-related herniation and low back pain. By pinpointing specific biological targets, the screening of smallmolecule compounds with significant clinical implications can be facilitated. This translational innovation promises to optimize cells communication within intervertebral disc microenvironment via localized drug delivery, potentially improving patient outcomes and satisfaction following spinal fusion or discectomy surgeries.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"30-43"},"PeriodicalIF":5.9,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931269","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":"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":"New developments in osteoporosis, osteoarthritis and soft tissue repair.","authors":"Gang Li","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":"A1-A2"},"PeriodicalIF":5.9,"publicationDate":"2024-11-22","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}