title: TNF-α-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis.
abstract: The incomplete understanding of aberrant neovascularization, which contributes to osteoarthritis suggests that additional modulators have yet to be identified. Our objective was to identify the role of Leucine-rich-alpha-2-glycoprotein1 (LRG1), a new regulator of pathogenic angiogenesis, in osteoarthritis progression and to develop effective treatment strategies. In this study, immunohistochemistry showed that LRG1 was increased in the subchondral bone and articular cartilage in anterior cruciate ligament transection (ACLT) mice. Further studies were focused on the role of LRG1 in osteoarthritis. Results showed that LRG1 promoted angiogenesis and mesenchymal stem cells (MSC) migration, which contribute to aberrant bone formation in the subchondral bone. Moreover, tumor necrosis factor-α (TNF-α), not interleukin-1β (IL-1β), IL-6 or IL-17, induced the LRG1 expression in human umbilical vein endothelial cells and this effect was inhibited by p38 mitogen-activated protein kinase or NF-κB inhibitor. Notably, inhibition of TNF-α and LRG1 activity by Lenalidomide, an inhibitor of TNF-α production, in ACLT mice attenuated degeneration of osteoarthritis articular cartilage. This study shows that TNF-α is the predominant proinflammatory cytokine that induces the secretion of LRG1. LRG1 contributes to angiogenesis-coupled de novo bone formation by increasing angiogenesis and recruiting MSCs in the subchondral bone of osteoarthritis joints. Inhibition of TNF-α and LRG1 by Lenalidomide could be a potential therapeutic approach.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chuandong
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences, Shanghai 200031, China.|Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200011, China.
authors.forename: Kerong
authors.initials: K
authors.lastname: Dai
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS); University of Chinese Academy of Sciences, Shanghai 200031, China.|Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200011, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002465:Cell Movement; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; C015246:LRG1 protein, human; C530631:LRG1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D000077269:Lenalidomide