Journal of Orthopaedic Translation最新文献

{"title":"FOXO1-mTOR pathway in vascular pericyte regulates the formation of type H vessels to control bone metabolism","authors":"Caiyu Cheng , Mingye Deng , Chubin Cheng , Hangtian Wu , Yutian Wang , Mincheng Lu , Zilong Yao , Kaiqun Li , Xianrong Zhang , Bin Yu","doi":"10.1016/j.jot.2024.08.010","DOIUrl":"10.1016/j.jot.2024.08.010","url":null,"abstract":"<div><h3>Background</h3><div>As the population aging progresses, age-related osteoporosis has become one of the most common and severe chronic degenerative diseases. Due to insufficient understanding of its complex pathomechanisms, current clinical treatments often suffer from many negative effects. Type H vessels play critical role in bone remodeling owing to their specialized function in coupling angiogenesis and osteogenesis. Increasing evidences have shown a close association between the age-related decline of type H vessels and bone loss. However, the underlying mechanisms whereby the regression of type H vessels with aging remain largely unknown.</div></div><div><h3>Methods</h3><div><em>Col2-Cre</em><sup><em>ERT</em></sup><em>/Foxo1</em><sup><em>flox/flox</em></sup> mice and FOXO1 inhibitor (AS1842856) treated adult (6 months) and middle aged (10 months) mice were utilized for evaluating the variations in bone volume, bone microarchitecture and type H vessels through micro-CT scanning analysis, histological staining and immunofluorescence staining. <em>In vitro</em> tube-forming and scratch assays were applied to evaluate the angiogenic capacity of human umbilical vein endothelial cells (HUVECs) exposed to AS1842856 or conditioned culture milieu of Human Brain Vascular Pericytes (HBVPs). The expression of pericyte marker proteins, myofibroblast-related proteins and genes in inhibitors-stimulated HBVPs were detected via western blot analysis and Reverse transcription-quantitative PCR (RT-qPCR). Furthermore, perivascular myofibroblastic-like transformation was confirmed in AS1842856-treated animal models through immunofluorescence staining. We also constructed <em>Adipoq-Cre/Foxo1</em><sup><em>flox/flox</em></sup> conditional knockout mice and measured their bone mass and type H vessels by micro-CT and immunofluorescence staining. Mechanistic experiments <em>in vitro</em> were conducted via detection of mTOR signalling expression in HBVPs with pharmacological intervention (AS1842856 and rapamycin), genetic knockdown of <em>Foxo1</em>, or FOXO1-overexpression plasmid treatment, verified by RT-qPCR, western blot analysis and cellular immunofluorescence staining. <em>In vivo</em> validation was conducted on <em>Adipoq-Cre/Foxo1</em><sup><em>flox/flox</em></sup> mice using immunofluorescence staining. Finally, alterations in osteo-morphology and type H vessels were verified in AS1842856-treated and rapamycin-treated aged mouse models.</div></div><div><h3>Results</h3><div>This study identified FOXO1 in pericytes as key components for the formation of type H vessels. We found that FOXO1 expression in pericytes decreases with aging, and pharmacological blocking with AS1842856 promoted type H vessels degeneration and increased bone loss in adult and middle-aged mice, while rapamycin prevented the above pathology in middle-aged mice. We further showed that the loss of FOXO1 in <em>Adipoq</em><sup>+</sup> pericytes led to degeneration of type H vessels","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"49 ","pages":"Pages 246-263"},"PeriodicalIF":5.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526266","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":"Emerging role of liver-bone axis in osteoporosis","authors":"Hongliang Gao ,&nbsp;Xing Peng ,&nbsp;Ning Li ,&nbsp;Liming Gou ,&nbsp;Tao Xu ,&nbsp;Yuqi Wang ,&nbsp;Jian Qin ,&nbsp;Hui Liang ,&nbsp;Peiqi Ma ,&nbsp;Shu Li ,&nbsp;Jing Wu ,&nbsp;Xihu Qin ,&nbsp;Bin Xue","doi":"10.1016/j.jot.2024.07.008","DOIUrl":"10.1016/j.jot.2024.07.008","url":null,"abstract":"<div><h3>Background</h3><p>Increasing attention to liver-bone crosstalk has spurred interest in targeted interventions for various forms of osteoporosis. Liver injury induced by different liver diseases can cause an imbalance in bone metabolism, indicating a novel regulatory paradigm between the liver and bone. However, the role of the liver-bone axis in both primary and secondary osteoporosis remains inadequately elucidated. Therefore, exploring the exact regulatory mechanisms of the liver-bone axis may offer innovative clinical approaches for treating diseases associated with the liver and bone.</p></div><div><h3>Methods</h3><p>Here, we summarize the latest research on the liver-bone axis by searching the PubMed and Web of Science databases and discuss the possible mechanism of the liver-bone axis in different types of osteoporosis. The literature directly reporting the regulatory role of the liver-bone axis in different types of osteoporosis from the PubMed and Web of Science databases has been included in the discussion of this review (including but not limited to the definition of the liver-bone axis, clinical studies, and basic research). In addition, articles discussing changes in bone metabolism caused by different etiologies of liver injury have also been included in the discussion of this review (including but not limited to clinical studies and basic research).</p></div><div><h3>Results</h3><p>Several endocrine factors (IGF-1, FGF21, hepcidin, vitamin D, osteocalcin, OPN, LCAT, Fetuin-A, PGs, BMP2/9, IL-1/6/17, and TNF-α) and key genes (SIRT2, ABCB4, ALDH2, TFR2, SPTBN1, ZNF687 and SREBP2) might be involved in the regulation of the liver-bone axis. In addition to the classic metabolic pathways involved in inflammation and oxidative stress, iron metabolism, cholesterol metabolism, lipid metabolism and immunometabolism mediated by the liver-bone axis require more research to elucidate the regulatory mechanisms involved in osteoporosis.</p></div><div><h3>Conclusion</h3><p>During primary and secondary osteoporosis, the liver-bone axis is responsible for liver and bone homeostasis via several hepatokines and osteokines as well as biochemical signaling. Combining multiomics technology and data mining technology could further advance our understanding of the liver-bone axis, providing new clinical strategies for managing liver and bone-related diseases.</p><p><strong>The translational potential of this article</strong> is as follows: Abnormal metabolism in the liver could seriously affect the metabolic imbalance of bone. This review summarizes the indispensable role of several endocrine factors and biochemical signaling pathways involved in the liver-bone axis and emphasizes the important role of liver metabolic homeostasis in the pathogenesis of osteoporosis, which provides novel potential directions for the prevention, diagnosis, and treatment of liver and bone-related diseases.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 217-231"},"PeriodicalIF":5.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000767/pdfft?md5=81f2e7a9c2b6b979ad8cbbfc8d695bf8&pid=1-s2.0-S2214031X24000767-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136530","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":"Biomarkers for hypertrophic chondrocyte differentiation are associated with spatial cellular organisation and suggest endochondral ossification-like processes in osteoarthritic cartilage: An exploratory study","authors":"Julius Michael Wolfgart ,&nbsp;Lea Cathrine Grötzner ,&nbsp;Sascha Hemayatkar-Fink ,&nbsp;Maik Schwitalle ,&nbsp;Florian Christof Bonnaire ,&nbsp;Martina Feierabend ,&nbsp;Marina Danalache ,&nbsp;Ulf Krister Hofmann","doi":"10.1016/j.jot.2024.08.006","DOIUrl":"10.1016/j.jot.2024.08.006","url":null,"abstract":"<div><h3>Background</h3><p>In healthy articular cartilage, chondrocytes are found along arcades of collagen fibers as Single Strings. With onset of cartilage degeneration this pattern changes to Double Strings. In the course of osteoarthritis Small Clusters, and finally Big Clusters form. In highly degenerated articular cartilage, another poorly understood pattern is found where chondrocyte morphology differs considerably, and the distribution of cells is diffuse. Progression of osteoarthritis is accompanied by key processes such as chondrocyte proliferation, apoptosis, hypertrophic differentiation, inflammation, and angiogenesis. The aim of this exploratory study was to identify biomarkers for these processes in the context of spatial cellular organizational changes in articular cartilage.</p></div><div><h3>Methods</h3><p>Cartilage explants (n = 166 patients) were sorted according to their predominant cellular pattern. Quantitative or semi-quantitative analysis of 39 biomarkers were performed by multiplex assay (31) or ELISA (8), and qualitative analysis on 12 immunohistochemical markers.</p></div><div><h3>Results</h3><p>Hypertrophic differentiation (e.g. type-X collagen, osteopontin, osteocalcin and interleukin-6) and angiogenesis were associated with changes in chondrocyte organisation. First changes take place already at the transition from Single Strings to Double Strings. Drastic changes in the appearance of numerous biomarkers are found at the transition from Big Clusters to Diffuse.</p></div><div><h3>Conclusion</h3><p>Key processes in osteoarthritis and their biomarkers seem to depend on the spatial distribution of chondrocytes in articular cartilage. Abrupt changes in biomarker occurrence were observed between Big Clusters and Diffuse insinuating that the Diffuse pattern is composed of a different cell population or at least a different form of chondrocyte morphology.</p></div><div><h3>The Translational Potential of this Article</h3><p>In situ identification of the different spatial chondrocyte patterns by fluorescence microscopy has already been established in the recent past. Analysing human in-situ cartilage explants rather than isolated OA chondrocytes closes the gap between in vitro and in vivo studies and as such, stretches a big step towards translation of the observed findings. The direct association between tissue biomarker profile and cellular arrangements representing different states of OA sheds new light on the molecular and cellular physiopathology, especially in the context of larger processes such as angiogenesis, cellular proliferation, differentiation, and apoptosis. This also opens an interesting perspective for future investigation of such biomarkers and processes in clinical studies.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 232-243"},"PeriodicalIF":5.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000937/pdfft?md5=2300829e74c4b5b2ff19c1bba55a0590&pid=1-s2.0-S2214031X24000937-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142229907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to ‘JD-312 – A novel small molecule that facilitates cartilage repair and alleviates osteoarthritis progression’[Journal of Orthopaedic Translation 44 (2024) 60–71]","authors":"Jingduo Gao ,&nbsp;Haixiang Pei ,&nbsp;Fang Lv ,&nbsp;Xin Niu ,&nbsp;Yu You ,&nbsp;Liang He ,&nbsp;Shijia Hu ,&nbsp;Karan M. Shah ,&nbsp;Mingyao Liu ,&nbsp;Yihua Chen ,&nbsp;Bing Du ,&nbsp;Hai Xiong ,&nbsp;Jian Luo","doi":"10.1016/j.jot.2024.08.017","DOIUrl":"10.1016/j.jot.2024.08.017","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 244-246"},"PeriodicalIF":5.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24001049/pdfft?md5=f2fe10427d493a4bb5c7e32136af2778&pid=1-s2.0-S2214031X24001049-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142310294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Sirt1 protects against intervertebral disc degeneration induced by 1,25-Dihydroxyvitamin D insufficiency in mice by inhibiting the NF-κB inflammatory pathway”[Journal of Orthopaedic Translation 40 (2023) 13–26]","authors":"Peng Wang ,&nbsp;Cuicui Yang ,&nbsp;Jinhong Lu ,&nbsp;Yongxin Ren ,&nbsp;David Goltzman ,&nbsp;Dengshun Miao","doi":"10.1016/j.jot.2024.08.019","DOIUrl":"10.1016/j.jot.2024.08.019","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"48 ","pages":"Pages 247-253"},"PeriodicalIF":5.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24001062/pdfft?md5=25ef67a88727873a459e713e0a3e0239&pid=1-s2.0-S2214031X24001062-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142310291","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":"Addressing musculoskeletal disorders through new treatment strategies","authors":"Heng Sun,&nbsp;Bin Li,&nbsp;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 ,&nbsp;Yuxuan Du ,&nbsp;Zejiu Tan ,&nbsp;Dongpeng Li ,&nbsp;Jiang Xie","doi":"10.1016/j.jot.2024.08.008","DOIUrl":"10.1016/j.jot.2024.08.008","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Ovariectomized (OVX) mice were employed as an &lt;em&gt;in vivo&lt;/em&gt; model of osteoclastogenesis. H&amp;E staining and micro-CT detected the histological changes and bone parameters in the femur tissues. RANKL-treated macrophages were used as the &lt;em&gt;in vitro&lt;/em&gt; 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&lt;sup&gt;6&lt;/sup&gt;A modification of &lt;em&gt;HOXA5&lt;/em&gt;. Luciferase and ChIP assays were employed to detect the direct association between HOXA5 and &lt;em&gt;WNK1&lt;/em&gt; promoter in macrophages.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;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&lt;sup&gt;6&lt;/sup&gt;A modification stabilized &lt;em&gt;HOXA5&lt;/em&gt; mRNA and increased its expression, and HOXA5 regulated &lt;em&gt;WNK1&lt;/em&gt; 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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;METTL14-mediated &lt;em&gt;HOXA5&lt;/em&gt; m&lt;sup&gt;6&lt;/sup&gt;A modification increased its expression, thereby inducing &lt;em&gt;WNK1&lt;/em&gt; 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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The Translational Potential of this Article·&lt;/h3&gt;&lt;p&gt;&lt;/p&gt;&lt;ul&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;p&gt;METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis in macrophages.·&lt;/p&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;p&gt;METTL14-mediated m6A modification stabilized HOXA5 mRNA and increased its expression.&lt;/p&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;p&gt;HOXA5 regulated WNK1 expression via direct binding to its promoter.&lt;/p&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;p&gt;Silencing of WNK1 reversed METTL14- or HOXA5-suppressed pyroptosis and macrophageosteoclast differentiation.·&lt;/p&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;p&gt;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 ,&nbsp;Ke He ,&nbsp;Junyu Zhu ,&nbsp;Xiaoxiao Li ,&nbsp;Xuan Wu ,&nbsp;Chao Zeng ,&nbsp;Guanghua Lei ,&nbsp;Ning Wang ,&nbsp;Hui Li ,&nbsp;Jie Wei","doi":"10.1016/j.jot.2024.08.007","DOIUrl":"10.1016/j.jot.2024.08.007","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;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&lt;sup&gt;INK4a&lt;/sup&gt; 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 &lt;em&gt;in vitro&lt;/em&gt; and &lt;em&gt;in vivo&lt;/em&gt;. 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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;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).&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;p&gt;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}