Pub Date : 2024-05-01DOI: 10.1016/j.jot.2024.02.009
Yu Miao , Shenghui Wu , Ziling Gong , Yiwei Chen , Feng Xue , Kexin Liu , Jian Zou , Yong Feng , Guangyi Li
Objectives
SPARCL1 is a matricellular protein that mediates the cell–matrix interactions and participates in physiological processes such as cell adhesion, differentiation and proliferation. However, its role in chondrocyte and osteoarthritis (OA) progression has not been fully characterized. We aimed to evaluate the effects of SPARCL1 on OA through in vitro and in vivo experiments.
Methods
Expression of SPARCL1 was examined in 55 paired human OA samples. Effects of Sparcl1 on chondrocytes were identified in vitro. Intra-articular injection was performed in an anterior cruciate ligament transection (ACLT) mouse model. Alterations of SPARCL1-mediated signaling pathway were identified by RNA-seq analysis. qPCR and western-blot were used to demonstrate the potential signaling pathway.
Results
SPARCL1 expression in the OA cartilage was increased compared with undamaged cartilage. Recombinant Sparcl1 protein induced extracellular matrix degradation in chondrocytes. Furthermore, intra-articular injection of recombinant Sparcl1 protein in ACLT mice could promote OA pathogenesis. Mechanistically, Sparcl1 activated TNF/NF-κB pathway and consequently led to increased transcription of inflammatory factors and catabolism genes of cartilage, which could be reversed by NF-κB inhibitor BAY 11–7082.
Conclusion
SPARCL1 could promote extracellular matrix degradation and inflammatory response to accelerate OA progression via TNF/NF-κB pathway.
The translational potential of this article
The current research could help to gain further insights into the underlying molecular mechanism in OA development, and provides a biological rationale for the use of SPARCL1 as a potential therapeutic target of OA.
目的SPARCL1是一种介导细胞与基质相互作用的母细胞蛋白,参与细胞粘附、分化和增殖等生理过程。然而,它在软骨细胞和骨关节炎(OA)进展中的作用尚未完全定性。我们旨在通过体外和体内实验评估 SPARCL1 对 OA 的影响。在体外确定了 Sparcl1 对软骨细胞的影响。在前十字韧带横断(ACLT)小鼠模型中进行关节内注射。结果SPARCL1在OA软骨中的表达与未受损软骨相比有所增加。重组 Sparcl1 蛋白诱导软骨细胞中细胞外基质的降解。此外,在 ACLT 小鼠关节内注射重组 Sparcl1 蛋白可促进 OA 发病。结论Sparcl1可通过TNF/NF-κB途径促进细胞外基质降解和炎症反应,从而加速OA的进展。本文的转化潜力目前的研究有助于进一步深入了解 OA 发生发展的潜在分子机制,并为将 SPARCL1 作为 OA 的潜在治疗靶点提供了生物学依据。
{"title":"SPARCL1 promotes chondrocytes extracellular matrix degradation and inflammation in osteoarthritis via TNF/NF-κB pathway","authors":"Yu Miao , Shenghui Wu , Ziling Gong , Yiwei Chen , Feng Xue , Kexin Liu , Jian Zou , Yong Feng , Guangyi Li","doi":"10.1016/j.jot.2024.02.009","DOIUrl":"https://doi.org/10.1016/j.jot.2024.02.009","url":null,"abstract":"<div><h3>Objectives</h3><p>SPARCL1 is a matricellular protein that mediates the cell–matrix interactions and participates in physiological processes such as cell adhesion, differentiation and proliferation. However, its role in chondrocyte and osteoarthritis (OA) progression has not been fully characterized. We aimed to evaluate the effects of SPARCL1 on OA through in vitro and <em>in vivo</em> experiments.</p></div><div><h3>Methods</h3><p>Expression of SPARCL1 was examined in 55 paired human OA samples. Effects of Sparcl1 on chondrocytes were identified in vitro. Intra-articular injection was performed in an anterior cruciate ligament transection (ACLT) mouse model. Alterations of SPARCL1-mediated signaling pathway were identified by RNA-seq analysis. qPCR and western-blot were used to demonstrate the potential signaling pathway.</p></div><div><h3>Results</h3><p>SPARCL1 expression in the OA cartilage was increased compared with undamaged cartilage. Recombinant Sparcl1 protein induced extracellular matrix degradation in chondrocytes. Furthermore, intra-articular injection of recombinant Sparcl1 protein in ACLT mice could promote OA pathogenesis. Mechanistically, Sparcl1 activated TNF/NF-κB pathway and consequently led to increased transcription of inflammatory factors and catabolism genes of cartilage, which could be reversed by NF-κB inhibitor BAY 11–7082.</p></div><div><h3>Conclusion</h3><p>SPARCL1 could promote extracellular matrix degradation and inflammatory response to accelerate OA progression via TNF/NF-κB pathway.</p></div><div><h3>The translational potential of this article</h3><p>The current research could help to gain further insights into the underlying molecular mechanism in OA development, and provides a biological rationale for the use of SPARCL1 as a potential therapeutic target of OA.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000287/pdfft?md5=effeaf6d49eea846f1d729be0ef9b128&pid=1-s2.0-S2214031X24000287-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141164440","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}
Pub Date : 2024-05-01DOI: 10.1016/j.jot.2024.03.007
Qianjin Wang , Can Cui , Ning Zhang , Wujian Lin , Senlin Chai , Simon Kwoon-Ho Chow , Ronald Man Yeung Wong , Yong Hu , Sheung Wai Law , Wing-Hoi Cheung
The neuromuscular junction (NMJ) is a specialized chemical synapse that converts neural impulses into muscle action. Age-associated NMJ degeneration, which involves nerve terminal and postsynaptic decline, denervation, and loss of motor units, significantly contributes to muscle weakness and dysfunction. Although physical training has been shown to make substantial modifications in NMJ of both young and aged animals, the results are often influenced by methodological variables in existing studies. Moreover, there is still lack of strong consensus on the specific effects of exercise on improving the morphology and function of the ageing NMJ. Consequently, the purpose of this study was to conduct a systematic review to elucidate the effects of exercise training on NMJ compartments in the elderly.
We conducted a systematic review using PubMed, Embase, and Web of Science databases, employing relevant keywords. Two independent reviewers selected studies that detailed NMJ changes during exercise in ageing, written in English, and available in full text.
In total, 20 papers were included. We examined the altered adaptation of the NMJ to exercise, focusing on presynaptic and postsynaptic structures and myofibers in older animals or humans. Our findings indicated that aged NMJs exhibited different adaptive responses to physical exercise compared to younger counterparts. Endurance training, compared with resistance and voluntary exercise regimens, was found to have a more pronounced effect on NMJ structural remodeling, particularly in fast twitch muscle fibers. Physical exercise was observed to promote the formation and maintenance of acetylcholine receptor (AChR) clusters by increasing the recombinant docking protein 7 (Dok7) expression and stabilizing Agrin and lipoprotein receptor-related protein 4 (LRP4). These insights suggest that research on exercise-related therapies could potentially attenuate the progression of neuromuscular degeneration.
Translational potential of this article: This systematic review provides a detailed overview of the effects of different types of physical exercise on improving NMJ in the elderly, providing scientific support for the timely intervention of muscle degeneration in the elderly by physical exercise, and providing help for the development of new therapeutic interventions in the future.
{"title":"Effects of physical exercise on neuromuscular junction degeneration during ageing: A systematic review","authors":"Qianjin Wang , Can Cui , Ning Zhang , Wujian Lin , Senlin Chai , Simon Kwoon-Ho Chow , Ronald Man Yeung Wong , Yong Hu , Sheung Wai Law , Wing-Hoi Cheung","doi":"10.1016/j.jot.2024.03.007","DOIUrl":"https://doi.org/10.1016/j.jot.2024.03.007","url":null,"abstract":"<div><p>The neuromuscular junction (NMJ) is a specialized chemical synapse that converts neural impulses into muscle action. Age-associated NMJ degeneration, which involves nerve terminal and postsynaptic decline, denervation, and loss of motor units, significantly contributes to muscle weakness and dysfunction. Although physical training has been shown to make substantial modifications in NMJ of both young and aged animals, the results are often influenced by methodological variables in existing studies. Moreover, there is still lack of strong consensus on the specific effects of exercise on improving the morphology and function of the ageing NMJ. Consequently, the purpose of this study was to conduct a systematic review to elucidate the effects of exercise training on NMJ compartments in the elderly.</p><p>We conducted a systematic review using PubMed, Embase, and Web of Science databases, employing relevant keywords. Two independent reviewers selected studies that detailed NMJ changes during exercise in ageing, written in English, and available in full text.</p><p>In total, 20 papers were included. We examined the altered adaptation of the NMJ to exercise, focusing on presynaptic and postsynaptic structures and myofibers in older animals or humans. Our findings indicated that aged NMJs exhibited different adaptive responses to physical exercise compared to younger counterparts. Endurance training, compared with resistance and voluntary exercise regimens, was found to have a more pronounced effect on NMJ structural remodeling, particularly in fast twitch muscle fibers. Physical exercise was observed to promote the formation and maintenance of acetylcholine receptor (AChR) clusters by increasing the recombinant docking protein 7 (Dok7) expression and stabilizing Agrin and lipoprotein receptor-related protein 4 (LRP4). These insights suggest that research on exercise-related therapies could potentially attenuate the progression of neuromuscular degeneration.</p><p>Translational potential of this article: This systematic review provides a detailed overview of the effects of different types of physical exercise on improving NMJ in the elderly, providing scientific support for the timely intervention of muscle degeneration in the elderly by physical exercise, and providing help for the development of new therapeutic interventions in the future.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X2400038X/pdfft?md5=aca3649b019d26e1fcc498c32afe81ce&pid=1-s2.0-S2214031X2400038X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141083807","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}
Pub Date : 2024-05-01DOI: 10.1016/j.jot.2024.03.003
Yang Shen , Haoming Wang , Hongwei Xie , Jiateng Zhang , Qingliang Ma , Shiyu Wang , Putao Yuan , Hong Xue , Huaxing Hong , Shunwu Fan , Wenbin Xu , Ziang Xie
Background
Osteoporosis is one of the most common bone diseases in middle-aged and elderly populations worldwide. The development of new drugs to treat the disease is a key focus of research. Current treatments for osteoporosis are mainly directed at promoting osteoblasts and inhibiting osteoclasts. However, there is currently no ideal approach for osteoporosis treatment. l-arginine is a semi-essential amino acid involved in a number of cellular processes, including nitric production, protein biosynthesis, and immune responses. We previously reported that l-arginine-derived compounds can play a regulatory role in bone homeostasis.
Purpose
To investigate the specific effect of l-arginine on bone homeostasis.
Methods
Mildly aged and ovariectomized mouse models were used to study the effects of l-arginine on osteogenesis and angiogenesis, assessed by micro-computed tomography and immunostaining of bone tissue. The effect of l-arginine on osteogenesis, angiogenesis, and adipogenesis was further studied in vitro using osteoblasts obtained from cranial cap bone, endothelial cells, and an adipogenic cell line. Specific methods to assess these processes included lipid staining, cell migration, tube-forming, and wound-healing assays. Protein and mRNA expression was determined for select biomarkers.
Results
We found that l-arginine attenuated bone loss and promoted osteogenesis and angiogenesis. l-arginine increased the activity of vascular endothelial cells, whereas it inhibited adipogenesis in vitro. In addition, we found that l-arginine altered the expression of PINK1/Parkin and Bnip3 in the mitochondria of osteoblast-lineage and endothelial cells, thereby promoting mitophagy and protecting cells from ROS. Similarly, l-arginine treatment effectively ameliorated osteoporosis in an ovariectomized mouse model.
Conclusion
l-arginine promotes angio-osteogenesis, and inhibits adipogenesis, effects mediated by the PINK1/Parkin- and Bnip3-mediated mitophagy.
The Translational Potential of this Article
L-arginine supplementation may be an effective adjunct therapy in the treatment of osteoporosis.
{"title":"l-arginine promotes angio-osteogenesis to enhance oxidative stress-inhibited bone formation by ameliorating mitophagy","authors":"Yang Shen , Haoming Wang , Hongwei Xie , Jiateng Zhang , Qingliang Ma , Shiyu Wang , Putao Yuan , Hong Xue , Huaxing Hong , Shunwu Fan , Wenbin Xu , Ziang Xie","doi":"10.1016/j.jot.2024.03.003","DOIUrl":"https://doi.org/10.1016/j.jot.2024.03.003","url":null,"abstract":"<div><h3>Background</h3><p>Osteoporosis is one of the most common bone diseases in middle-aged and elderly populations worldwide. The development of new drugs to treat the disease is a key focus of research. Current treatments for osteoporosis are mainly directed at promoting osteoblasts and inhibiting osteoclasts. However, there is currently no ideal approach for osteoporosis treatment. <span>l</span>-arginine is a semi-essential amino acid involved in a number of cellular processes, including nitric production, protein biosynthesis, and immune responses. We previously reported that <span>l</span>-arginine-derived compounds can play a regulatory role in bone homeostasis.</p></div><div><h3>Purpose</h3><p>To investigate the specific effect of <span>l</span>-arginine on bone homeostasis.</p></div><div><h3>Methods</h3><p>Mildly aged and ovariectomized mouse models were used to study the effects of <span>l</span>-arginine on osteogenesis and angiogenesis, assessed by micro-computed tomography and immunostaining of bone tissue. The effect of <span>l</span>-arginine on osteogenesis, angiogenesis, and adipogenesis was further studied in vitro using osteoblasts obtained from cranial cap bone, endothelial cells, and an adipogenic cell line. Specific methods to assess these processes included lipid staining, cell migration, tube-forming, and wound-healing assays. Protein and mRNA expression was determined for select biomarkers.</p></div><div><h3>Results</h3><p>We found that <span>l</span>-arginine attenuated bone loss and promoted osteogenesis and angiogenesis. <span>l</span>-arginine increased the activity of vascular endothelial cells, whereas it inhibited adipogenesis in vitro. In addition, we found that <span>l</span>-arginine altered the expression of PINK1/Parkin and Bnip3 in the mitochondria of osteoblast-lineage and endothelial cells, thereby promoting mitophagy and protecting cells from ROS. Similarly, <span>l</span>-arginine treatment effectively ameliorated osteoporosis in an ovariectomized mouse model.</p></div><div><h3>Conclusion</h3><p><span>l</span>-arginine promotes angio-osteogenesis, and inhibits adipogenesis, effects mediated by the PINK1/Parkin- and Bnip3-mediated mitophagy.</p></div><div><h3>The Translational Potential of this Article</h3><p>L-arginine supplementation may be an effective adjunct therapy in the treatment of osteoporosis.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000275/pdfft?md5=f778df8bd039a297ac9ffe9d86a22309&pid=1-s2.0-S2214031X24000275-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141073076","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}
Pub Date : 2024-05-01DOI: 10.1016/j.jot.2024.03.005
Xingzhi Jing , Wenchao Wang , Xining He , Xiaoyang Liu , Xiaoxia Yang , Cheng Su , Yuandong Shao , Zhongpeng Ge , Heran Wang , Xingang Cui
Backgroud
Iron overload is a prevalent condition in the elderly, often associated with various degenerative diseases, including intervertebral disc degeneration (IDD). Nevertheless, the mechanisms responsible for iron ion accumulation in tissues and the mechanism that regulate iron homeostasis remain unclear. Transferrin receptor-1 (TFR1) serves as the primary cellular iron gate, playing a pivotal role in controlling intracellular iron levels, however its involvement in IDD pathogenesis and the underlying mechanism remains obscure.
Methods
Firstly, IDD mice model was established to determine the iron metabolism associated proteins changes during IDD progression. Then CEP chondrocytes were isolated and treated with TBHP or pro-inflammatory cytokines to mimic pathological environment, western blotting, immunofluorescence assay and tissue staining were employed to explore the underlying mechanisms. Lastly, TfR1 siRNA and Feristatin II were employed and the degeneration of IDD was examined using micro-CT and immunohistochemical analysis.
Results
We found that the IDD pathological environment, characterized by oxidative stress and pro-inflammatory cytokines, could enhance iron influx by upregulating TFR1 expression in a HIF-2α dependent manner. Excessive iron accumulation not only induces chondrocytes ferroptosis and exacerbates oxidative stress, but also triggers the innate immune response mediated by c-GAS/STING, by promoting mitochondrial damage and the release of mtDNA. The inhibition of STING through siRNA or the reduction of mtDNA replication using ethidium bromide alleviated the degeneration of CEP chondrocytes induced by iron overload.
Conclusion
Our study systemically explored the role of TFR1 mediated iron homeostasis in IDD and its underlying mechanisms, implying that targeting TFR1 to maintain balanced iron homeostasis could offer a promising therapeutic approach for IDD management.
The translational potential of this article
Our study demonstrated the close link between iron metabolism dysfunction and IDD, indicated that targeting TfR1 may be a novel therapeutic strategy for IDD.
{"title":"HIF-2α/TFR1 mediated iron homeostasis disruption aggravates cartilage endplate degeneration through ferroptotic damage and mtDNA release: A new mechanism of intervertebral disc degeneration","authors":"Xingzhi Jing , Wenchao Wang , Xining He , Xiaoyang Liu , Xiaoxia Yang , Cheng Su , Yuandong Shao , Zhongpeng Ge , Heran Wang , Xingang Cui","doi":"10.1016/j.jot.2024.03.005","DOIUrl":"https://doi.org/10.1016/j.jot.2024.03.005","url":null,"abstract":"<div><h3>Backgroud</h3><p>Iron overload is a prevalent condition in the elderly, often associated with various degenerative diseases, including intervertebral disc degeneration (IDD). Nevertheless, the mechanisms responsible for iron ion accumulation in tissues and the mechanism that regulate iron homeostasis remain unclear. Transferrin receptor-1 (TFR1) serves as the primary cellular iron gate, playing a pivotal role in controlling intracellular iron levels, however its involvement in IDD pathogenesis and the underlying mechanism remains obscure.</p></div><div><h3>Methods</h3><p>Firstly, IDD mice model was established to determine the iron metabolism associated proteins changes during IDD progression. Then CEP chondrocytes were isolated and treated with TBHP or pro-inflammatory cytokines to mimic pathological environment, western blotting, immunofluorescence assay and tissue staining were employed to explore the underlying mechanisms. Lastly, TfR1 siRNA and Feristatin II were employed and the degeneration of IDD was examined using micro-CT and immunohistochemical analysis.</p></div><div><h3>Results</h3><p>We found that the IDD pathological environment, characterized by oxidative stress and pro-inflammatory cytokines, could enhance iron influx by upregulating TFR1 expression in a HIF-2α dependent manner. Excessive iron accumulation not only induces chondrocytes ferroptosis and exacerbates oxidative stress, but also triggers the innate immune response mediated by c-GAS/STING, by promoting mitochondrial damage and the release of mtDNA. The inhibition of STING through siRNA or the reduction of mtDNA replication using ethidium bromide alleviated the degeneration of CEP chondrocytes induced by iron overload.</p></div><div><h3>Conclusion</h3><p>Our study systemically explored the role of TFR1 mediated iron homeostasis in IDD and its underlying mechanisms, implying that targeting TFR1 to maintain balanced iron homeostasis could offer a promising therapeutic approach for IDD management.</p></div><div><h3>The translational potential of this article</h3><p>Our study demonstrated the close link between iron metabolism dysfunction and IDD, indicated that targeting TfR1 may be a novel therapeutic strategy for IDD.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000305/pdfft?md5=f696ffc796d7be98460c6e42e3ab5f8d&pid=1-s2.0-S2214031X24000305-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077742","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}
Pub Date : 2024-05-01DOI: 10.1016/j.jot.2024.04.003
Guangyang Xie , Cheng Huang , Shide Jiang , Hengzhen Li , Yihan Gao , Tingwei Zhang , Qidong Zhang , Volotovski Pavel , Masoud Rahmati , Yusheng Li
Smoking continues to pose a global threat to morbidity and mortality in populations. The detrimental impact of smoking on health and disease includes bone destruction and immune disruption in various diseases. Osteoimmunology, which explores the communication between bone metabolism and immune homeostasis, aims to reveal the interaction between the osteoimmune systems in disease development. Smoking impairs the differentiation of mesenchymal stem cells and osteoblasts in bone formation while promoting osteoclast differentiation in bone resorption. Furthermore, smoking stimulates the Th17 response to increase inflammatory and osteoclastogenic cytokines that promote the receptor activator of NF-κB ligand (RANKL) signaling in osteoclasts, thus exacerbating bone destruction in periodontitis and rheumatoid arthritis. The pro-inflammatory role of smoking is also evident in delayed bone fracture healing and osteoarthritis development. The osteoimmunological therapies are promising in treating periodontitis and rheumatoid arthritis, but further research is still required to block the smoking-induced aggravation in these diseases.
Translational potential
This review summarizes the adverse effect of smoking on mesenchymal stem cells, osteoblasts, and osteoclasts and elucidates the smoking-induced exacerbation of periodontitis, rheumatoid arthritis, bone fracture healing, and osteoarthritis from an osteoimmune perspective. We also propose the therapeutic potential of osteoimmunological therapies for bone destruction aggravated by smoking.
{"title":"Smoking and osteoimmunology: Understanding the interplay between bone metabolism and immune homeostasis","authors":"Guangyang Xie , Cheng Huang , Shide Jiang , Hengzhen Li , Yihan Gao , Tingwei Zhang , Qidong Zhang , Volotovski Pavel , Masoud Rahmati , Yusheng Li","doi":"10.1016/j.jot.2024.04.003","DOIUrl":"https://doi.org/10.1016/j.jot.2024.04.003","url":null,"abstract":"<div><p>Smoking continues to pose a global threat to morbidity and mortality in populations. The detrimental impact of smoking on health and disease includes bone destruction and immune disruption in various diseases. Osteoimmunology, which explores the communication between bone metabolism and immune homeostasis, aims to reveal the interaction between the osteoimmune systems in disease development. Smoking impairs the differentiation of mesenchymal stem cells and osteoblasts in bone formation while promoting osteoclast differentiation in bone resorption. Furthermore, smoking stimulates the Th17 response to increase inflammatory and osteoclastogenic cytokines that promote the receptor activator of NF-κB ligand (RANKL) signaling in osteoclasts, thus exacerbating bone destruction in periodontitis and rheumatoid arthritis. The pro-inflammatory role of smoking is also evident in delayed bone fracture healing and osteoarthritis development. The osteoimmunological therapies are promising in treating periodontitis and rheumatoid arthritis, but further research is still required to block the smoking-induced aggravation in these diseases.</p></div><div><h3>Translational potential</h3><p>This review summarizes the adverse effect of smoking on mesenchymal stem cells, osteoblasts, and osteoclasts and elucidates the smoking-induced exacerbation of periodontitis, rheumatoid arthritis, bone fracture healing, and osteoarthritis from an osteoimmune perspective. We also propose the therapeutic potential of osteoimmunological therapies for bone destruction aggravated by smoking.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000408/pdfft?md5=7dd412068790f6c6e18184d3ae4dd30b&pid=1-s2.0-S2214031X24000408-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140906543","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}
Pub Date : 2024-05-01DOI: 10.1016/j.jot.2023.10.004
Shu Jia , Tao Yang , Sheng Gao , Luyue Bai , Zhiguo Zhu , Siqi Zhao , Yexin Wang , Xiao Liang , Yanpeng Li , Longfei Gao , Zifang Zhang , Xu Gao , Dongru Li , Shang Chen , Bin Zhang , Chunyang Meng
Background
Reactive oxygen species (ROS), predominantly generated by mitochondria, play a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). Reduction of ROS levels may be an effective strategy to delay IVDD. In this study, we assessed whether umbilical cord mesenchymal stem cell-exosomes (UCMSC-exos) can be used to treat IVDD by suppressing ROS production caused by mitochondrial dysfunction.
Materials and methods
Human UCMSC-exos were isolated and identified. Nucleus pulposus cells (NPCs) were stimulated with H2O2 in the presence or absence of exosomes. Then, 4D label free quantitative (4D-LFQ) proteomics were used to analyze the differentially expressed (DE) proteins. Mitochondrial membrane potential (MMP), mitochondrial ROS and protein levels were determined via immunofluorescence staining, flow cytometry and western blotting respectively. Additionally, high-throughput sequencing was performed to identify the DE miRNAs in NPCs. Finally, therapeutic effects of UCMSC-exos were investigated in a puncture-induced IVDD rat model. Degenerative grades of rat IVDs were assessed using magnetic resonance imaging and histochemical staining.
Results
UCMSC-exos effectively improved the viability of NPCs and restored the expression of the extracellular matrix (ECM) proteins, collagen type II alpha-1 (COL2A1) and matrix metalloproteinase-13 induced by H2O2. Additionally, UCMSC-exos not only reduced the total intracellular ROS and mitochondrial superoxide levels, but also increased MMP in pathological NPCs. 4D-LFQ proteomics and western blotting further revealed that UCMSC-exos up-regulated the levels of the mitochondrial protein, mitochondrial transcription factor A (TFAM), in H2O2-induced NPCs. High-throughput sequencing and qRT-PCR uncovered that UCMSC-exos down-regulated the levels of miR-194-5p, a potential negative regulator of TFAM, induced by H2O2. Finally, in vivo results showed that UCMSC-exos injection improved the histopathological structure and enhanced the expression levels of COL2A1 and TFAM in the rat IVDD model.
Conclusions
Our findings suggest that UCMSC-exos promote ECM synthesis, relieve mitochondrial oxidative stress, and attenuate mitochondrial dysfunction in vitro and in vivo, thereby effectively treating IVDD.
The translational potential of this article
This study provides solid experimental data support for the therapeutic effects of UCMSC-exos on IVDD, suggesting that UCMSC-exos will be a promising nanotherapy for IVDD.
{"title":"Exosomes from umbilical cord mesenchymal stem cells ameliorate intervertebral disc degeneration via repairing mitochondrial dysfunction","authors":"Shu Jia , Tao Yang , Sheng Gao , Luyue Bai , Zhiguo Zhu , Siqi Zhao , Yexin Wang , Xiao Liang , Yanpeng Li , Longfei Gao , Zifang Zhang , Xu Gao , Dongru Li , Shang Chen , Bin Zhang , Chunyang Meng","doi":"10.1016/j.jot.2023.10.004","DOIUrl":"https://doi.org/10.1016/j.jot.2023.10.004","url":null,"abstract":"<div><h3>Background</h3><p>Reactive oxygen species (ROS), predominantly generated by mitochondria, play a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). Reduction of ROS levels may be an effective strategy to delay IVDD. In this study, we assessed whether umbilical cord mesenchymal stem cell-exosomes (UCMSC-exos) can be used to treat IVDD by suppressing ROS production caused by mitochondrial dysfunction.</p></div><div><h3>Materials and methods</h3><p>Human UCMSC-exos were isolated and identified. Nucleus pulposus cells (NPCs) were stimulated with H<sub>2</sub>O<sub>2</sub> in the presence or absence of exosomes. Then, 4D label free quantitative (4D-LFQ) proteomics were used to analyze the differentially expressed (DE) proteins. Mitochondrial membrane potential (MMP), mitochondrial ROS and protein levels were determined via immunofluorescence staining, flow cytometry and western blotting respectively. Additionally, high-throughput sequencing was performed to identify the DE miRNAs in NPCs. Finally, therapeutic effects of UCMSC-exos were investigated in a puncture-induced IVDD rat model. Degenerative grades of rat IVDs were assessed using magnetic resonance imaging and histochemical staining.</p></div><div><h3>Results</h3><p>UCMSC-exos effectively improved the viability of NPCs and restored the expression of the extracellular matrix (ECM) proteins, collagen type II alpha-1 (COL2A1) and matrix metalloproteinase-13 induced by H<sub>2</sub>O<sub>2</sub>. Additionally, UCMSC-exos not only reduced the total intracellular ROS and mitochondrial superoxide levels, but also increased MMP in pathological NPCs. 4D-LFQ proteomics and western blotting further revealed that UCMSC-exos up-regulated the levels of the mitochondrial protein, mitochondrial transcription factor A (TFAM), in H<sub>2</sub>O<sub>2</sub>-induced NPCs. High-throughput sequencing and qRT-PCR uncovered that UCMSC-exos down-regulated the levels of miR-194-5p, a potential negative regulator of TFAM, induced by H<sub>2</sub>O<sub>2</sub>. Finally, in vivo results showed that UCMSC-exos injection improved the histopathological structure and enhanced the expression levels of COL2A1 and TFAM in the rat IVDD model.</p></div><div><h3>Conclusions</h3><p>Our findings suggest that UCMSC-exos promote ECM synthesis, relieve mitochondrial oxidative stress, and attenuate mitochondrial dysfunction in vitro and in vivo, thereby effectively treating IVDD.</p></div><div><h3>The translational potential of this article</h3><p>This study provides solid experimental data support for the therapeutic effects of UCMSC-exos on IVDD, suggesting that UCMSC-exos will be a promising nanotherapy for IVDD.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X23000785/pdfft?md5=0a997da267908804c9efffd0d3e9cb85&pid=1-s2.0-S2214031X23000785-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156292","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}
Pub Date : 2024-03-01DOI: 10.1016/j.jot.2024.02.001
Yangkang Zheng , Pengyu Wang , Li Zhao , Lianping Xing , Hao Xu , Ning Li , Yongjian Zhao , Qi Shi , Qianqian Liang , YongJun Wang
Background
The musculoskeletal system contains an extensive network of lymphatic vessels. Decreased lymph flow of the draining collecting lymphatics usually occurs in clinic after traumatic fractures. However, whether defects in lymphatic drainage can affect fracture healing is unclear.
Methods
To investigate the effect of lymphatic dysfunction on fracture healing, we used a selective VEGFR3 tyrosine kinase inhibitor to treat tibial fractured mice for 5 weeks versus a vehicle-treated control. To ensure successfully establishing deceased lymphatic drainage model for fractured mice, we measured lymphatic clearance by near infrared indocyanine green lymphatic imaging (NIR-ICG) and the volume of the draining popliteal lymph nodes (PLNs) by ultrasound at the whole phases of fracture healing. In addition, hindlimb edema from day 0 to day 7 post-fracture, pain sensation by Hargreaves test at day 1 post-fracture, bone histomorphometry by micro-CT and callus composition by Alcian Blue-Hematoxylin/Orange G staining at day 14 post-fracture, and bone quality by biomechanical testing at day 35 post-fracture were applied to evaluate fracture healing. To promote fracture healing via increasing lymphatic drainage, we then treated fractured mice with anti-mouse podoplanin (PDPN) neutralizing antibody or isotype IgG antibody for 1 week to observe lymphatic drainage function and assess bone repair as methods described above.
Results
Compared to vehicle-treated group, SAR-treatment group significantly decreased lymphatic clearance and the volume of draining PLNs. SAR-treatment group significantly increased soft tissue swelling, and reduced bone volume (BV)/tissue volume (TV), trabecular number (Tb.N), woven bone and biomechanical properties of fracture callus. In addition, anti-PDPN treated group significantly reduced the number of CD41+ platelets in PLNs and increased the number of pulsatile lymphatic vessels, lymphatic clearance and the volume of PLNs. Moreover, anti-PDPN treated group significantly reduced hindlimb edema and pain sensation and increased BV/TV, trabecular number (Tb.Th), woven bone and biomechanical properties of fracture callus.
Conclusions
Inhibition of proper lymphatic drainage function delayed fracture healing. Use of a anti-PDPN neutralizing antibody reduced lymphatic platelet thrombosis (LPT), increased lymphatic drainage and improved fracture healing.
The translational potential of this article
(1) We demonstrated lymphatic drainage function is crucial for fracture healing. (2) To unblock the lymphatic drainage and prevent the risk of bleeding and mortality by blood thinner, we demonstrated PDPN neutralizing antibody is a novel and safe way forward in the treatment of bone fracture healing by eliminating LPT and increasing lymphatic drainage.
{"title":"A novel therapy for fracture healing by increasing lymphatic drainage","authors":"Yangkang Zheng , Pengyu Wang , Li Zhao , Lianping Xing , Hao Xu , Ning Li , Yongjian Zhao , Qi Shi , Qianqian Liang , YongJun Wang","doi":"10.1016/j.jot.2024.02.001","DOIUrl":"https://doi.org/10.1016/j.jot.2024.02.001","url":null,"abstract":"<div><h3>Background</h3><p>The musculoskeletal system contains an extensive network of lymphatic vessels. Decreased lymph flow of the draining collecting lymphatics usually occurs in clinic after traumatic fractures. However, whether defects in lymphatic drainage can affect fracture healing is unclear.</p></div><div><h3>Methods</h3><p>To investigate the effect of lymphatic dysfunction on fracture healing, we used a selective VEGFR3 tyrosine kinase inhibitor to treat tibial fractured mice for 5 weeks versus a vehicle-treated control. To ensure successfully establishing deceased lymphatic drainage model for fractured mice, we measured lymphatic clearance by near infrared indocyanine green lymphatic imaging (NIR-ICG) and the volume of the draining popliteal lymph nodes (PLNs) by ultrasound at the whole phases of fracture healing. In addition, hindlimb edema from day 0 to day 7 post-fracture, pain sensation by Hargreaves test at day 1 post-fracture, bone histomorphometry by micro-CT and callus composition by Alcian Blue-Hematoxylin/Orange G staining at day 14 post-fracture, and bone quality by biomechanical testing at day 35 post-fracture were applied to evaluate fracture healing. To promote fracture healing via increasing lymphatic drainage, we then treated fractured mice with anti-mouse podoplanin (PDPN) neutralizing antibody or isotype IgG antibody for 1 week to observe lymphatic drainage function and assess bone repair as methods described above.</p></div><div><h3>Results</h3><p>Compared to vehicle-treated group, SAR-treatment group significantly decreased lymphatic clearance and the volume of draining PLNs. SAR-treatment group significantly increased soft tissue swelling, and reduced bone volume (BV)/tissue volume (TV), trabecular number (Tb.N), woven bone and biomechanical properties of fracture callus. In addition, anti-PDPN treated group significantly reduced the number of CD41<sup>+</sup> platelets in PLNs and increased the number of pulsatile lymphatic vessels, lymphatic clearance and the volume of PLNs. Moreover, anti-PDPN treated group significantly reduced hindlimb edema and pain sensation and increased BV/TV, trabecular number (Tb.Th), woven bone and biomechanical properties of fracture callus.</p></div><div><h3>Conclusions</h3><p>Inhibition of proper lymphatic drainage function delayed fracture healing. Use of a anti-PDPN neutralizing antibody reduced lymphatic platelet thrombosis (LPT), increased lymphatic drainage and improved fracture healing.</p></div><div><h3>The translational potential of this article</h3><p>(1) We demonstrated lymphatic drainage function is crucial for fracture healing. (2) To unblock the lymphatic drainage and prevent the risk of bleeding and mortality by blood thinner, we demonstrated PDPN neutralizing antibody is a novel and safe way forward in the treatment of bone fracture healing by eliminating LPT and increasing lymphatic drainage.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000147/pdfft?md5=42170eb64192690edc2f138fdd8bc4fd&pid=1-s2.0-S2214031X24000147-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140113370","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}
Pub Date : 2024-03-01DOI: 10.1016/j.jot.2023.10.007
Guidong Shi , Nakagawa Koichi , Rou Wan , Yicun Wang , Ramona Reisdorf , Abigayle Wilson , Tony C.T. Huang , Peter C. Amadio , Alexander Meves , Chunfeng Zhao , Steven L. Moran
Background
Prevention of adhesion formation following flexor tendon repair is essential for restoration of normal finger function. Although many medications have been studied in the experimental setting to prevent adhesions, clinical application is limited due to the complexity of application and delivery in clinical translation.
Methods
In this study, optimal dosages of gelatin and pentamidine were validated by gelatin concentration test. Following cell viability, cell migration, live and dead cell, and cell adhesion assay of the Turkey tenocytes, a model of Turkey tendon repair was established to evaluate the effectiveness of the Pentamidine-Gelatin sheet.
Results
Pentamidine carried with gelatin, a Food and drug administration (FDA) approved material for drug delivery, showed good dynamic release, biocompatibility, and degradation. The optimal dose of pentamidine (25ug) was determined in the in vivo study using tenocyte viability, migration, and cell adhesion assays. Further biochemical analyses demonstrated that this positive effect may be due to pentamidine downregulating the Wnt signaling pathway without affecting collagen expression.
Conclusions
We tested a FDA-approved antibiotic, pentamidine, for reducing adhesion formation after flexor tendon repair in both in vitro and in vivo using a novel turkey animal model. Compared with the non-pentamidine treatment group, pentamidine treated turkeys had significantly reduced adhesions and improved digit function after six weeks of tendon healing.
The translational potential of this article
This study for the first time showed that a common clinical drug, pentamidine, has a potential for clinical application to reduce tendon adhesions and improve tendon gliding function without interfering with tendon healing.
{"title":"Pentamidine-loaded gelatin decreases adhesion formation of flexor tendon","authors":"Guidong Shi , Nakagawa Koichi , Rou Wan , Yicun Wang , Ramona Reisdorf , Abigayle Wilson , Tony C.T. Huang , Peter C. Amadio , Alexander Meves , Chunfeng Zhao , Steven L. Moran","doi":"10.1016/j.jot.2023.10.007","DOIUrl":"https://doi.org/10.1016/j.jot.2023.10.007","url":null,"abstract":"<div><h3>Background</h3><p>Prevention of adhesion formation following flexor tendon repair is essential for restoration of normal finger function. Although many medications have been studied in the experimental setting to prevent adhesions, clinical application is limited due to the complexity of application and delivery in clinical translation.</p></div><div><h3>Methods</h3><p>In this study, optimal dosages of gelatin and pentamidine were validated by gelatin concentration test. Following cell viability, cell migration, live and dead cell, and cell adhesion assay of the Turkey tenocytes, a model of Turkey tendon repair was established to evaluate the effectiveness of the Pentamidine-Gelatin sheet.</p></div><div><h3>Results</h3><p>Pentamidine carried with gelatin, a Food and drug administration (FDA) approved material for drug delivery, showed good dynamic release, biocompatibility, and degradation. The optimal dose of pentamidine (25ug) was determined in the in vivo study using tenocyte viability, migration, and cell adhesion assays. Further biochemical analyses demonstrated that this positive effect may be due to pentamidine downregulating the Wnt signaling pathway without affecting collagen expression.</p></div><div><h3>Conclusions</h3><p>We tested a FDA-approved antibiotic, pentamidine, for reducing adhesion formation after flexor tendon repair in both in vitro and in vivo using a novel turkey animal model. Compared with the non-pentamidine treatment group, pentamidine treated turkeys had significantly reduced adhesions and improved digit function after six weeks of tendon healing.</p></div><div><h3>The translational potential of this article</h3><p>This study for the first time showed that a common clinical drug, pentamidine, has a potential for clinical application to reduce tendon adhesions and improve tendon gliding function without interfering with tendon healing.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X23000815/pdfft?md5=990e04692440c44b66e7ac4a9e275b9f&pid=1-s2.0-S2214031X23000815-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140113371","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}
Pub Date : 2024-03-01DOI: 10.1016/j.jot.2024.01.004
Qiang Shi , Yang Chen , Yan Xu , Can Chen , Hongbin Lu
Background
Anterior cruciate ligament (ACL) rupture is a common sports injury, which causes knee instability and abnormal joint kinematics. The current ACL graft was single-phasic, and not convenient for the formation of enthesis-like tissue in the bone tunnel, resulting in poor integration of graft-to-bone.
Methods
A band-shaped acellular tendon (BAT) was prepared as the core component of the ACL reconstruction graft at first, while sleeve-shaped acellular cartilage (SAC) or sleeve-shaped acellular bone (SAB) was fabricated using a vacuum aspiration system (VAS)-based decellularization protocol. The biocompatibility of the three acellular matrixes was evaluated. Furthermore, a collagen-binding peptide (CBP) derived from the A3 domain of von Willebrand factor was respectively fused into the N-terminal of GDF7, TGFβ3, or BMP2 to synthesize three recombinant growth factors capable of binding collagen (named C-GDF7, C-TGFβ3, or C-BMP2), which were respectively tethered to the BAT, SAC or SAB for improving their inducibilities in stem cell differentiation. An in-vitro experiment was performed to evaluate theirs osteogenic, chondrogenic, and tenogenic inducibilities. Then, C-TGFβ3-tethering SAC (C-TGFβ3@SAC) and C-BMP2-tethering SAB (C-BMP2@SAB) were sequentially surrounded at the bone tunnel part of C-GDF7-tethering BAT (C-GDF7@BAT), thus a sleeve-shaped acellular graft with a triphasic enthesis-like structure in bone tunnel part (named tissue-engineered graft, TE graft) was engineered. Lastly, a canine ACL reconstruction model was used to evaluate the in-vivo performance of this TE graft in enhancing graft-to-bone integration.
Results
The BAT, SAC, and SAB well preserved the structure and components of native tendon, cartilage, and bone, showing good biocompatibility. C-GDF7, C-TGFβ3, or C-BMP2 showed a stronger binding ability to BAT, SAC, and SAB. The C-GDF7@BAT, C-TGFβ3@SAC, or C-BMP2@SAB was a controlled delivery system for the scaffold-specific release of GDF7, TGFβ3, and BMP2, thus showing superior tenogenic, chondrogenic, or osteogenic inducibility, respectively. Using a canine ACL reconstruction model, abundant newly-formed bone and connective collagen fibers could be observed at the integration site between TE graft and bone tunnel at postoperative 16 weeks. Meanwhile, the failure load of the reconstructed ACL by TE graft was significantly higher than that of the autograft.
Conclusion
The TE graft could be used to reconstruct ruptured ACL and augment graft-to-bone integration, thus demonstrating high potential for clinical translation in ACL reconstruction.
Translational potential of this article
The findings of the study indicated that the TE graft could be a novel graft for ACL reconstruction with the ability to augment graft-to-bone integration, which may provide a foundation for future clinical application.
背景前交叉韧带(ACL)断裂是一种常见的运动损伤,会导致膝关节不稳定和关节运动学异常。方法首先制备带状非细胞肌腱(BAT)作为前交叉韧带重建移植物的核心成分,然后使用基于真空抽吸系统(VAS)的脱细胞方案制造套筒状非细胞软骨(SAC)或套筒状非细胞骨(SAB)。对这三种细胞基质的生物相容性进行了评估。此外,还分别在 GDF7、TGFβ3 或 BMP2 的 N 端融合了源自 von Willebrand 因子 A3 结构域的胶原结合肽(CBP),合成了三种能结合胶原的重组生长因子(分别命名为 C-GDF7、C-TGFβ3 或 C-BMP2),并将其分别系在 BAT、SAC 或 SAB 上,以提高它们在干细胞分化中的诱导性。体外实验评估了它们的成骨、成软骨和成腱诱导能力。然后,C-TGFβ3系链SAC(C-TGFβ3@SAC)和C-BMP2系链SAB(C-BMP2@SAB)依次被包围在C-GDF7系链BAT(C-GDF7@BAT)的骨隧道部分,从而在骨隧道部分形成了具有三相内植物样结构的套筒状无细胞移植物(命名为组织工程移植物,TE移植物)。结果 BAT、SAC 和 SAB 很好地保留了原生肌腱、软骨和骨的结构和成分,显示出良好的生物相容性。C-GDF7、C-TGFβ3 或 C-BMP2 与 BAT、SAC 和 SAB 的结合能力更强。C-GDF7@BAT、C-TGFβ3@SAC或C-BMP2@SAB是一种可控递送系统,可在支架特异性释放GDF7、TGFβ3和BMP2,从而分别显示出优异的成腱、成软骨或成骨诱导性。在犬前交叉韧带重建模型中,术后16周时可在TE移植物与骨隧道的结合部位观察到大量新形成的骨和结缔胶原纤维。结论TE移植物可用于重建断裂的前交叉韧带并增强移植物与骨的整合,因此在前交叉韧带重建的临床应用中具有很大的潜力。
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Pub Date : 2024-03-01DOI: 10.1016/j.jot.2024.01.008
Zan Li , Xiangchen Zeng , Baohong Shi , Jie Han , Zuoxing Wu , Xiaohui Chen , Long Zhang , Na Li , Matthew Greenblatt , Jianming Huang , Ren Xu
Background
Recently, the osteogenic potential of Adiponectin-labeled adipogenic lineage progenitors (Adipoq-lineage progenitors) in bone marrow has been observed to support bone maintenance and repair. However, little is known about the function of Schnurri-3 (SHN3, also known as HIVEP3) in other mesenchymal lineage cells, apart from its negative regulation of bone formation on osteoblasts.
Method
In this study, we used single-cell RNA sequencing (scRNA-seq) profiling to demonstrate that Adipoq-lineage progenitors express higher levels of Shn3 compared to other mesenchymal cell populations in mice and humans. To investigate the role of SHN3 in Adipoq-lineage progenitors, we generated a murine model specifically harboring a Shn3-deficient allele in Adipoq-expressing cells. Information of mice body weight was collected weekly to generate body weight curve. Bone phenotype was analyzed using micro-CT and histomorphometric studies. To eliminate the role of peripheral adipose tissue on bone, we collected adipose wet weight, performed intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests, and conducted a fat-transplantation study. Osteoblast and osteoclast functions were assessed through toluidine blue staining and TRAP staining, respectively. We further investigated the effect of Shn3 depletion on the differentiation of Adipoq-lineage progenitors through immunostaining and in vitro differentiation assays. Finally, we evaluated whether Shn3 deficiency in Adipoq-lineage progenitors affects the fracture healing process by generating bi-cortical femoral fracture models.
Results
Depletion of Shn3 in Adipoq-lineage progenitors resulted in a significant increase in trabecular bone mass and bone formation in vivo, without disrupting whole-body energy metabolism and skeletal development. Consistent with these findings, both cell-lineage tracing and functional assays revealed that Shn3 ablation effectively shifted the cell fate of Adipoq-lineage progenitors towards an osteogenic phenotype in the bone marrow. Furthermore, in vivo studies demonstrated that the lack of Shn3 in Adipoq-lineage progenitors also enhanced bone fracture healing under pathological conditions.
Conclusion
Overall, our findings provide a novel strategy for targeting the osteoanabolic potential of bone marrow Adipoq-lineage progenitors as a potential treatment for bone loss-related disorders.
Translational potential of this article
We have identified a novel gene target that directs the cell fate of a previously identified non-osteogenic cell population under physiological conditions. This study not only expands the therapeutic value of Shn3 ablation in treating osteoporotic or traumatic bone diseases but also provides new insights into the contribution of bone marrow Adipoq-lin
{"title":"Schnurri-3 controls osteogenic fate of Adipoq-lineage progenitors in bone marrow","authors":"Zan Li , Xiangchen Zeng , Baohong Shi , Jie Han , Zuoxing Wu , Xiaohui Chen , Long Zhang , Na Li , Matthew Greenblatt , Jianming Huang , Ren Xu","doi":"10.1016/j.jot.2024.01.008","DOIUrl":"https://doi.org/10.1016/j.jot.2024.01.008","url":null,"abstract":"<div><h3>Background</h3><p>Recently, the osteogenic potential of Adiponectin-labeled adipogenic lineage progenitors (Adipoq-lineage progenitors) in bone marrow has been observed to support bone maintenance and repair. However, little is known about the function of Schnurri-3 (SHN3, also known as HIVEP3) in other mesenchymal lineage cells, apart from its negative regulation of bone formation on osteoblasts.</p></div><div><h3>Method</h3><p>In this study, we used single-cell RNA sequencing (scRNA-seq) profiling to demonstrate that Adipoq-lineage progenitors express higher levels of <em>Shn3</em> compared to other mesenchymal cell populations in mice and humans. To investigate the role of SHN3 in Adipoq-lineage progenitors, we generated a murine model specifically harboring a Shn3-deficient allele in Adipoq-expressing cells. Information of mice body weight was collected weekly to generate body weight curve. Bone phenotype was analyzed using micro-CT and histomorphometric studies. To eliminate the role of peripheral adipose tissue on bone, we collected adipose wet weight, performed intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests, and conducted a fat-transplantation study. Osteoblast and osteoclast functions were assessed through toluidine blue staining and TRAP staining, respectively. We further investigated the effect of Shn3 depletion on the differentiation of Adipoq-lineage progenitors through immunostaining and <em>in vitro</em> differentiation assays. Finally, we evaluated whether <em>Shn3</em> deficiency in Adipoq-lineage progenitors affects the fracture healing process by generating bi-cortical femoral fracture models.</p></div><div><h3>Results</h3><p>Depletion of <em>Shn3</em> in Adipoq-lineage progenitors resulted in a significant increase in trabecular bone mass and bone formation <em>in vivo</em>, without disrupting whole-body energy metabolism and skeletal development. Consistent with these findings, both cell-lineage tracing and functional assays revealed that <em>Shn3</em> ablation effectively shifted the cell fate of Adipoq-lineage progenitors towards an osteogenic phenotype in the bone marrow. Furthermore, <em>in vivo</em> studies demonstrated that the lack of <em>Shn3</em> in Adipoq-lineage progenitors also enhanced bone fracture healing under pathological conditions.</p></div><div><h3>Conclusion</h3><p>Overall, our findings provide a novel strategy for targeting the osteoanabolic potential of bone marrow Adipoq-lineage progenitors as a potential treatment for bone loss-related disorders.</p></div><div><h3>Translational potential of this article</h3><p>We have identified a novel gene target that directs the cell fate of a previously identified non-osteogenic cell population under physiological conditions. This study not only expands the therapeutic value of Shn3 ablation in treating osteoporotic or traumatic bone diseases but also provides new insights into the contribution of bone marrow Adipoq-lin","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000196/pdfft?md5=6947b477e413f85ed1902eecfc399157&pid=1-s2.0-S2214031X24000196-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140192027","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}