Journal of Orthopaedic Translation最新文献

{"title":"Addressing musculoskeletal disorders through new treatment strategies","authors":"Heng Sun, Bin Li, Huilin Yang","doi":"10.1016/j.jot.2024.09.001","DOIUrl":"10.1016/j.jot.2024.09.001","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages A1-A2"},"PeriodicalIF":5.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24001128/pdfft?md5=95072c3fc6fa7f1148f91c5afd092014&pid=1-s2.0-S2214031X24001128-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142310293","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":"METTL14-mediated HOXA5 m6A modification alleviates osteoporosis via promoting WNK1 transcription to suppress NLRP3-dependent macrophage pyroptosis","authors":"Hao Tang , Yuxuan Du , Zejiu Tan , Dongpeng Li , Jiang Xie","doi":"10.1016/j.jot.2024.08.008","DOIUrl":"10.1016/j.jot.2024.08.008","url":null,"abstract":"<div><h3>Background</h3><p>Osteoporosis is a commonly diagnosed metabolic bone disease. NLRP3 inflammasome activation and pyroptosis are observed during osteoporosis. However, the mechanism by which NLRP3-mediated pyroptosis contributes to osteoporosis remains largely undefined.</p></div><div><h3>Methods</h3><p>Ovariectomized (OVX) mice were employed as an <em>in vivo</em> model of osteoclastogenesis. H&E staining and micro-CT detected the histological changes and bone parameters in the femur tissues. RANKL-treated macrophages were used as the <em>in vitro</em> model of osteoclastogenesis, and LPS/ATP treatment was used as the macrophage pyroptosis model. The cytotoxicity, cytokine secretion and caspase-1 activity were assessed by LDH release assay, ELISA and flow cytometry, respectively. The osteoclast formation ability was detected by TRAP staining. qRT-PCR, IHC and Western blotting detected the expression and localization of METTL14, pyroptosis-related or osteoclast-specific molecules in femur tissues or macrophages. Mechanistically, MeRIP assessed the m<sup>6</sup>A modification of <em>HOXA5</em>. Luciferase and ChIP assays were employed to detect the direct association between HOXA5 and <em>WNK1</em> promoter in macrophages.</p></div><div><h3>Results</h3><p>METTL14, HOXA5 and WNK1 were decreased in OVX mice, which was associated with pyroptosis. METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis, along with the upregulation of WNK1. METTL14-mediated m<sup>6</sup>A modification stabilized <em>HOXA5</em> mRNA and increased its expression, and HOXA5 regulated <em>WNK1</em> expression via direct binding to its promoter. Functional studies showed that WNK1 knockdown counteracted METTL14- or HOXA5-suppressed pyroptosis and macrophage-osteoclast differentiation. In OVX mice, overexpression of METTL14 or HOXA5 alleviated osteoporosis via suppressing WNK1-dependent NLRP3 signaling.</p></div><div><h3>Conclusion</h3><p>METTL14-mediated <em>HOXA5</em> m<sup>6</sup>A modification increased its expression, thereby inducing <em>WNK1</em> expression and suppressing NLRP3-dependent pyroptosis to alleviate osteoporosis. The combination of METTL14 or HOXA5 agonist with pyroptosis targeted therapy may be a promising therapeutic approach for osteoporosis.</p></div><div><h3>The Translational Potential of this Article·</h3><p></p><ul><li><span>•</span><span><p>METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis in macrophages.·</p></span></li><li><span>•</span><span><p>METTL14-mediated m6A modification stabilized HOXA5 mRNA and increased its expression.</p></span></li><li><span>•</span><span><p>HOXA5 regulated WNK1 expression via direct binding to its promoter.</p></span></li><li><span>•</span><span><p>Silencing of WNK1 reversed METTL14- or HOXA5-suppressed pyroptosis and macrophageosteoclast differentiation.·</p></span></li><li><span>•</span><span><p>METTL14 or HOXA5 over","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 190-203"},"PeriodicalIF":5.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000950/pdfft?md5=7eb5c8164c8519c68ffa80f040877e93&pid=1-s2.0-S2214031X24000950-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076678","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":"Memantine attenuates the development of osteoarthritis by blocking NMDA receptor mediated calcium overload and chondrocyte senescence","authors":"Qingmei Cheng , Ke He , Junyu Zhu , Xiaoxiao Li , Xuan Wu , Chao Zeng , Guanghua Lei , Ning Wang , Hui Li , Jie Wei","doi":"10.1016/j.jot.2024.08.007","DOIUrl":"10.1016/j.jot.2024.08.007","url":null,"abstract":"<div><h3>Background</h3><p>Memantine, which is an FDA-proven drug for the treatment of dementia, exerts its function by blocking the function of NMDA (N-methyl-D-aspartate) receptor, a calcium-permeable ion channel that reduces cytotoxic calcium overload. Chondrocyte senescence is a crucial cellular event that contributes to articular cartilage degeneration during osteoarthritis (OA) development. To date, the effects of memantine and its downstream NMDA receptor on chondrocyte senescence and OA have been rarely reported.</p></div><div><h3>Methods</h3><p>The protein levels of NMDA receptor and its agonistic ligand, glutamate, were compared between normal and OA chondrocytes. The quantity of intracellular calcium ions and the level of mitochondrial damage were evaluated using specific fluorescent probes and transmission electron microscopy (TEM), respectively. Chondrocyte senescence was evaluated by senescence-associated β-galactosidase (SA-β-Gal) staining and p16<sup>INK4a</sup> analysis. The function of NMDA receptor in chondrocyte senescence and OA was tested via agonists activation and gene knockdown experiments. The therapeutic effects of memantine on OA were examined both <em>in vitro</em> and <em>in vivo</em>. Additionally, to verify the findings from animal samples, a propensity score-matched cohort study was conducted using data from a United Kingdom primary care database (i.e., IQVIA Medical Research Database [IMRD]) to compare the risk of OA-related joint replacement involved in memantine initiators versus active comparators (i.e., acetylcholinesterase [AchE] initiators) in patients with dementia.</p></div><div><h3>Results</h3><p>The protein expression of NMDA receptor and the secretion of glutamate were both significantly increased in OA chondrocytes. NMDA receptor activation was found to stimulate chondrocyte calcium overload, which further led to mitochondrial fragmentation and chondrocyte senescence. Blocking the NMDA receptor with memantine and N-methyl-D-aspartate receptor subunit 1(NR1, the gene encoding NMDA receptor) knockdown resulted in reduced calcium influx, mitochondrial fragmentation, as well as cellular senescence in OA chondrocytes. Intra-articular injection of memantine in OA mice also exhibited protective effects against cartilage degeneration. Moreover, in the 1:5 propensity score-matched cohort study consisting of 6218 patients (n = 1435 in the memantine cohort; n = 4783 in the AchE cohort), the memantine initiator was associated with a lower risk of OA-related joint replacement than AchE initiators (Hazard ratio = 0.56, 95 % confidence interval: 0.34 to 0.99).</p></div><div><h3>Conclusion</h3><p>NMDA receptor plays an important role in inflammatory-induced cytotoxic calcium overload in chondrocytes, while memantine can effectively block the NMDA receptor to reduce chondrocyte senescence and retard the development of OA.</p></div><div><h3>The translational potential of this article</h3><p>As a clinically licensed dru","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 204-216"},"PeriodicalIF":5.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000949/pdfft?md5=92a97791c27d4e19aa50784cc9855641&pid=1-s2.0-S2214031X24000949-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142083728","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":"Advanced therapy with mesenchymal stromal cells for knee osteoarthritis: Systematic review and meta-analysis of randomized controlled trials","authors":"Caio Gomes Tabet ,&nbsp;Rafael Leite Pacheco ,&nbsp;Ana Luiza Cabrera Martimbianco ,&nbsp;Rachel Riera ,&nbsp;Arnaldo José Hernandez ,&nbsp;Daniela Franco Bueno ,&nbsp;Tiago Lazzaretti Fernandes","doi":"10.1016/j.jot.2024.07.012","DOIUrl":"10.1016/j.jot.2024.07.012","url":null,"abstract":"<div><h3>Background</h3><p>Advanced cell therapies emerged as promising candidates for treatment of knee articular diseases, but robust evidence regarding their clinical applicability is still lacking.</p></div><div><h3>Objective</h3><p>To assess the efficacy and safety of advanced mesenchymal stromal cells (MSC) therapy for knee osteoarthritis (OA) and chondral lesions.</p></div><div><h3>Methods</h3><p>Systematic review of randomized controlled trials conducted in accordance with Cochrane Handbook and reported following PRISMA checklist. GRADE approach was used for assessing the evidence certainty.</p></div><div><h3>Results</h3><p>25 randomized controlled trials that enrolled 1048 participants were included. Meta-analyses data showed that, compared to viscosupplementation (VS), advanced MSC therapy resulted in a 1.91 lower pain VAS score (95 % CI ‐3.23 to −0.59; p &lt; 0.00001) for the treatment of knee OA after 12 months. Compared to placebo, the difference was 0.99 lower pain VAS points (95 % CI ‐1.94 to −0.03; p = 0.76). According to the GRADE approach, the evidence was very uncertain for both comparisons. By excluding studies with high risk of bias, there was a similar size of effect (VAS MD ‐1.54, 95 % CI ‐2.09 to −0.98; p = 0.70) with improved (moderate) certainty of evidence, suggesting that MSC therapy probably reduces pain slightly better than VS. Regarding serious adverse events, there was no difference from advanced MSC therapy to placebo or to VS, with very uncertain evidence.</p></div><div><h3>Conclusion</h3><p>Advanced MSC therapy resulted in lower pain compared to placebo or VS for the treatment of knee OA after 12 months, with no difference in adverse events. However, the evidence was considered uncertain.</p></div><div><h3>The Translational Potential of this Article</h3><p>Currently, there is a lack of studies with good methodological structure aiming to evaluate the real clinical impact of advanced cell therapy for knee OA. The present study was well structured and conducted, with Risk of Bias, GRADE certainty assessment and sensitivity analysis. It explores the translational aspect of the benefits and safety of MSC compared with placebo and gold-standard therapy to give practitioners and researchers support to expand this therapy in their practice.</p></div><div><h3>PROSPERO registration number</h3><p>CRD42020158173. Access at <span><span>https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=158173</span><svg><path></path></svg></span>.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 176-189"},"PeriodicalIF":5.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X2400086X/pdfft?md5=476887109501e205d05ab6ce9e40b89f&pid=1-s2.0-S2214031X2400086X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076677","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":"Diagnosis and treatment of anterior cruciate ligament injuries: Consensus of Chinese experts part II: Graft selection and clinical outcome evaluation","authors":"Tianwu Chen ,&nbsp;Xizhuang Bai ,&nbsp;Lunhao Bai ,&nbsp;Wai Sin Chan ,&nbsp;Shiyi Chen ,&nbsp;Chen Chen ,&nbsp;Jiwu Chen ,&nbsp;Liaobin Chen ,&nbsp;Guofeng Dai ,&nbsp;Zhizeng Gao ,&nbsp;Yang Guo ,&nbsp;Yong Hu ,&nbsp;Ning Hu ,&nbsp;Huayang Huang ,&nbsp;Xunwu Huang ,&nbsp;Xuan Huang ,&nbsp;Jingmin Huang ,&nbsp;Yifan Kang ,&nbsp;Hung Maan Lee ,&nbsp;Hongyun Li ,&nbsp;Yongsheng Xu","doi":"10.1016/j.jot.2024.07.002","DOIUrl":"10.1016/j.jot.2024.07.002","url":null,"abstract":"<div><h3>Background</h3><p>In the recent decade, there has been substantial progress in the technologies and philosophies associated with diagnosing and treating anterior cruciate ligament (ACL) injuries in China. The therapeutic efficacy of ACL reconstruction in re-establishing the stability of the knee joint has garnered widespread acknowledgment. However, the path toward standardizing diagnostic and treatment protocols remains to be further developed and refined.</p></div><div><h3>Objective</h3><p>In this context, the Chinese Association of Orthopaedic Surgeons (CAOS) and the Chinese Society of Sports Medicine (CSSM) collaboratively developed an expert consensus on diagnosing and treating ACL injury, aiming to enhance medical quality through refining professional standards.</p></div><div><h3>Methods</h3><p>The consensus drafting team invited experts across the Greater China region, including the mainland, Hong Kong, Macau, and Taiwan, to formulate and review the consensus using a modified Delphi method as a standardization approach. As members of the CSSM Lower Limb Study Group and the CAOS Arthroscopy and Sports Medicine Study Group, invited experts concentrated on two pivotal issues: “Graft Selection” and “Clinical Outcome Evaluation” during the second part of the consensus development.</p></div><div><h3>Results</h3><p>This focused discussion ultimately led to a strong consensus on nine specific consensus terms.</p></div><div><h3>Conclusion</h3><p>The consensus clearly states that ACL reconstruction has no definitive “gold standard” graft choice. Autografts have advantages in healing capability but are limited in availability and have potential donor site morbidities; allografts reduce surgical trauma but incur additional costs, and there are concerns about slow healing, quality control issues, and a higher failure rate in young athletes; synthetic ligaments allow for early rehabilitation and fast return to sport, but the surgery is technically demanding and incurs additional costs. When choosing a graft, one should comprehensively consider the graft's characteristics, the doctor's technical ability, and the patient's needs. When evaluating clinical outcomes, it is essential to ensure an adequate sample size and follow-up rate, and the research should include patient subjective scoring, joint function and stability, complications, surgical failure, and the return to sport results. Medium and long-term follow-ups should not overlook the assessment of knee osteoarthritis.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 163-175"},"PeriodicalIF":5.9,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000706/pdfft?md5=20e7374d9702de439069a0719a042c13&pid=1-s2.0-S2214031X24000706-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044631","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":"Prevalence, risk factors, microbiological results and clinical outcome in unexpected positive intraoperative cultures in unclear and presumed aseptic hip and knee revision arthroplasties – A ten-year retrospective analysis with a minimum follow up of 2 years","authors":"Sebastian Simon ,&nbsp;Luca Martalanz ,&nbsp;Bernhard J.H. Frank ,&nbsp;Susana Gardete Hartmann ,&nbsp;Jennyfer A. Mitterer ,&nbsp;Sujeesh Sebastian ,&nbsp;Stephanie Huber ,&nbsp;Jochen G. Hofstaetter","doi":"10.1016/j.jot.2024.08.002","DOIUrl":"10.1016/j.jot.2024.08.002","url":null,"abstract":"<div><h3>Background</h3><p>The aim of this study was to assess the prevalence, microbiological spectrum, risk factors, and clinical outcomes of unexpected-positive-intraoperative-cultures (UPIC) in presumed aseptic and unclear revision-total-hip-/knee-arthroplasties (rTHA and rTKA) compared to culture-negative (CN) revisions.</p></div><div><h3>Methods</h3><p>This study reviewed all International-consensus-meeting-2018 (ICM 2018) negative or inconclusive rTHA (n = 751) and rTKA (n = 679) performed at our institution from 2011 to 2020 with a minimum follow-up of two years. A Kaplan-Meier-analysis was performed to determine the septic and aseptic-free implant survival in cases with UPIC's and matched culture-negative cases. Patient demographics, risk factors, microbiological spectrum and clinical outcomes were evaluated.</p></div><div><h3>Results</h3><p>There were significantly more UPIC cases in rTHA 196/751 (26.1 %) compared to rTKA 113/679 (16.6 %); (p &lt; 0.001). UPICs in rTKA and rTHA have a lower septic and aseptic implant-free-survival compared to CN revisions. Patients with a history of nickel allergy have a higher risk of an UPIC in rTHA and rTKA (p &lt; 0.001). Septic re-revisions after UPIC had a significantly (H: p = 0.004; K: p = 0.030) shorter time period to the primary/previous surgery (H: 84 (IQR:41–797); K: 115 (IQR:55–446)) compared to patients with aseptic re-revisions after UPIC (H:1248 (IQR:178-3534); K: 827 (IQR:361-1183)).</p></div><div><h3>Conclusion</h3><p>UPICs have a higher rate of septic and aseptic failure than CN outcomes. UPICs are twice as common in rTHA compared to rTKA. Preoperative PJI workup reduces the UPIC rate. Nickel allergy is a risk factor for UPIC. Early revisions with UPICs after primary THA or TKA have a higher risk of septic failure.</p></div><div><h3>The translational potential of this article</h3><p>This article provides new information on revision rates for UPIC and potential risk factors for UPIC and its treatment failure.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 156-162"},"PeriodicalIF":5.9,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000895/pdfft?md5=60db224076b882de5a10e78430714624&pid=1-s2.0-S2214031X24000895-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141997810","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":"Strontium zinc silicate simultaneously alleviates osteoporosis and sarcopenia in tail-suspended rats via Piezo1-mediated Ca2+ signaling","authors":"Lingwei Huang ,&nbsp;Yiren Jiao ,&nbsp;Hangbin Xia ,&nbsp;Huili Li ,&nbsp;Jing Yu ,&nbsp;Yumei Que ,&nbsp;Zhen Zeng ,&nbsp;Chen Fan ,&nbsp;Chen Wang ,&nbsp;Chen Yang ,&nbsp;Jiang Chang","doi":"10.1016/j.jot.2024.07.014","DOIUrl":"10.1016/j.jot.2024.07.014","url":null,"abstract":"<div><h3>Background</h3><p>Long-term physical inactivity probably leads to a co-existence of osteoporosis and sarcopenia which result in a high risk of falls, fractures, disability and even mortality. However, universally applicable and feasible approaches are lacking in the concurrent treatment of osteoporosis and sarcopenia. In this study, we evaluated the effect of strontium zinc silicate bioceramic (SZS) extract on osteoporosis and sarcopenia and explored its underlying mechanisms.</p></div><div><h3>Methods</h3><p>Hindlimb osteoporosis and sarcopenia were established in a tail-suspended rat model. The bones were conducted μCT scanning, histological examination, and gene expression analysis, and the muscles were conducted histological examination and gene expression analysis. <em>In vitro,</em> the effect of SZS extract on osteoblasts was determined by alizarin red S staining, immunofluorescence and qPCR. Similarly, the effect of SZS extract on myoblasts was determined by immunofluorescence and qPCR.. At last, the role of Piezo1 and the change of intracellular calcium ion (Ca²⁺) were explored through blockading the Piezo1 by GsMTx4 in MC3T3-E1 and C2C12 cells, respectively.</p></div><div><h3>Results</h3><p>We found that SZS extract could concurrently and efficiently prevent bone structure deterioration, muscle atrophy and fibrosis in hind limbs of the tail-suspended rats. The <em>in vivo</em> study also showed that SZS extract could upregulate the mRNA expression of Piezo1, thereby maintaining the homeostasis of bones and muscles. <em>In vitro</em> study demonstrated that SZS extract could promote the proliferation and differentiation of MC3T3-E1 and C2C12 cells by increasing the intracellular Ca²⁺ in a Piezo1-dependent manner.</p></div><div><h3>Conclusion</h3><p>This study demonstrated that SZS extract could increase Piezo1-mediated intracellular Ca²⁺, and facilitate osteogenic differentiation of osteoblast and myogenic differentiation of myoblasts, contributing to alleviation of osteoporosis and sarcopenia in a tail-suspended rat model.</p></div><div><h3>The translational potential of this article</h3><p>The current study might provide a universally applicable and efficient strategy to treat musculoskeletal disorders based on bioactive ceramics. The verification of the role of Piezo1-modulated intracellular Ca²⁺ during osteogenesis and myogenesis provided a possible therapeutic target against mechanical related diseases.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 146-155"},"PeriodicalIF":5.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000883/pdfft?md5=108fcca703d7d99942f6d66c0baf037c&pid=1-s2.0-S2214031X24000883-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141979040","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":"Phillygenin inhibits neuroinflammation and promotes functional recovery after spinal cord injury via TLR4 inhibition of the NF-κB signaling pathway","authors":"Yu Zhang ,&nbsp;Shining Xiao ,&nbsp;Fan Dan ,&nbsp;Geliang Yao ,&nbsp;Shu'e Hong ,&nbsp;Jiaming Liu ,&nbsp;Zhili Liu","doi":"10.1016/j.jot.2024.07.013","DOIUrl":"10.1016/j.jot.2024.07.013","url":null,"abstract":"<div><h3>Background</h3><p>Spinal cord injuries (SCIs) trigger a cascade of detrimental processes, encompassing neuroinflammation and oxidative stress (OS), ultimately leading to neuronal damage. Phillygenin (PHI), isolated from forsythia, is used in a number of biomedical applications, and is known to exhibit anti-neuroinflammation activity. In this study, we investigated the role and mechanistic ability of PHI in the activation of microglia-mediated neuroinflammation and subsequent neuronal apoptosis following SCI.</p></div><div><h3>Methods</h3><p>A rat model of SCI was used to investigate the impact of PHI on inflammation, axonal regeneration, neuronal apoptosis, and the restoration of motor function. <em>In vitro</em>, neuroinflammation models were induced by stimulating microglia with lipopolysaccharide (LPS); then, we investigated the influence of PHI on pro-inflammatory mediator release in LPS-treated microglia along with the underlying mechanisms. Finally, we established a co-culture system, featuring microglia and VSC 4.1 cells, to investigate the role of PHI in the activation of microglia-mediated neuronal apoptosis.</p></div><div><h3>Results</h3><p><em>In vivo</em>, PHI significantly inhibited the inflammatory response and neuronal apoptosis while enhancing axonal regeneration and improving motor function recovery. <em>In vitro,</em> PHI inhibited the release of inflammation-related factors from polarized BV2 cells in a dose-dependent manner. The online Swiss Target Prediction database predicted that toll-like receptor 4 (TLR4) was the target protein for PHI. In addition, Molecular Operating Environment software was used to perform molecular docking for PHI with the TLR4 protein; this resulted in a binding energy interaction of −6.7 kcal/mol. PHI inhibited microglia-mediated neuroinflammation, the production of reactive oxygen species (ROS), and activity of the NF-κb signaling pathway. PHI also increased mitochondrial membrane potential (MMP) in VSC 4.1 neuronal cells. In BV2 cells, PHI attenuated the overexpression of TLR4-induced microglial polarization and significantly suppressed the release of inflammatory cytokines.</p></div><div><h3>Conclusion</h3><p>PHI ameliorated SCI-induced neuroinflammation by modulating the TLR4/MYD88/NF-κB signaling pathway. PHI has the potential to be administered as a treatment for SCI and represents a novel candidate drug for addressing neuroinflammation mediated by microglial cells.</p></div><div><h3>The translational potential of this article</h3><p>We demonstrated that PHI is a potential drug candidate for the therapeutic management of SCI with promising developmental and translational applications.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 133-145"},"PeriodicalIF":5.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000858/pdfft?md5=9725131673a30662a4fc91b5d60a92a0&pid=1-s2.0-S2214031X24000858-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141930903","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":"Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies","authors":"Yi Zou,&nbsp;Changyu Liu,&nbsp;Zhenggang Wang,&nbsp;Guanghui Li,&nbsp;Jun Xiao","doi":"10.1016/j.jot.2024.07.010","DOIUrl":"10.1016/j.jot.2024.07.010","url":null,"abstract":"<div><p>Pain is the leading symptom for most individuals with osteoarthritis (OA), a complex condition marked by joint discomfort. Recently, the dynamic interplay between the nervous and immune systems has become a focal point for understanding pain regulation. Despite this, there is still a substantial gap in our comprehensive understanding of the neuroimmune interactions and their effects on pain in OA. This review examines the bidirectional influences between immune cells and nerves in OA progression. It explores current approaches that target neuroimmune pathways, including promoting M2 macrophage polarization and specific neuronal receptor targeting, for effective pain reduction.</p></div><div><h3>Translational potential statement</h3><p>This review provides a comprehensive overview of the mechanisms underlying the interplay between the immune system and nervous system during the progression of OA, as well as their contributions to pain. Additionally, it compiles existing intervention strategies targeting neuroimmunity for the treatment of OA pain. This information offers valuable insights for researchers seeking to address the challenge of OA pain.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 123-132"},"PeriodicalIF":5.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000834/pdfft?md5=9519f147b0595becb63ec5dce52cd1fd&pid=1-s2.0-S2214031X24000834-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141930906","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":"Treatment effects, adverse outcomes and cardiovascular safety of romosozumab – Existing worldwide data: A systematic review and meta-analysis","authors":"Ronald Man Yeung Wong,&nbsp;Pui Yan Wong,&nbsp;Chaoran Liu,&nbsp;Hei Yuet Wong,&nbsp;Man Ki Fong,&nbsp;Ning Zhang,&nbsp;Wing Hoi Cheung,&nbsp;Sheung Wai Law","doi":"10.1016/j.jot.2024.07.011","DOIUrl":"10.1016/j.jot.2024.07.011","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Romosozumab is a novel monoclonal antibody that binds to sclerostin, and has dual effects of increasing bone formation and decreasing bone resorption, giving it a unique mechanism of action. The objective of this study was to perform a systematic review and meta-analysis based on existing worldwide data on treatment effects and safety of romosozumab in randomized controlled trials.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;A systematic search was carried out on four databases including PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL). The keywords used for search was “(romosozumab) AND (osteoporosis OR safety)”. Randomized controlled trial or post-hoc studies of the included randomized controlled trial which studied the effects and safety of romosozumab were included. The quality of selected studies was assessed with the Cochrane collaboration tool and the PEDro scale.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;20 studies were included for qualitative analysis. 14 studies were included for meta-analysis. In total, there were 13,507 (n = 13,507) participants with 637 men and 12,870 women from original cohorts. The overall mean difference was in favor of romosozumab treatment for lumbar spine (10.04 (95 % confidence interval (CI) = 7.51–12.57; p &lt; 0.00001)), total hip (4.04 (95 % CI = 3.10–4.99; p &lt; 0.00001)) and femoral neck bone mineral density (3.77 (95 % CI = 2.90–4.64; p &lt; 0.00001)) at 12 months. There was significantly less likelihood of new vertebral fractures with romosozumab compared to control (odds ratio (OR) 0.42 (95 % CI = 0.20–0.89); p = 0.02) at 12 months of treatment. There was significantly less likelihood of new vertebral fracture at 24 months with 12 months of romosozumab followed by sequential treatment with anti-resorptive compared to control with only anti-resorptive agent use (OR 0.36 (95 % CI = 0.18–0.71); p = 0.003). There was no significant difference in serious adverse events and fatal adverse events with use of romosozumab compared with control in our meta-analyses. There were no significant differences in serious cardiovascular events in Asian population of romosozumab with control group with 12 months of romosozumab treatment followed by 24 months of anti-resorptive agent with OR 1.09 (95 % CI = 0.40–2.96; P = 0.86). There was no significant difference between romosozumab group and control group for the median time to radiographic healing. Our qualitative analysis on Quantitative Computed Tomography (QCT), Finite element analysis (FEA) and bone biopsy analyses demonstrated that romosozumab improved parameters and measures in these domains as well.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;In conclusion, our study showed that romosozumab was an effective agent to treat osteoporosis with high quality evidence. There were no significant differences in the adverse events, serious adverse events, fatal adverse events identified. Further subgroup analysis of cardiovascula","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 107-122"},"PeriodicalIF":5.9,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000846/pdfft?md5=c082cecae230e71276e7e24236e393f5&pid=1-s2.0-S2214031X24000846-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141930905","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}