Wang Yiyun, Xu Jiajia, Zhang Xudong, Wang Chuandong, Huang Yan, Dai Kerong, Zhang Xiaoling
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.
Cell Death Dis. 2017 Mar 30;8(3):e2715. doi: 10.1038/cddis.2017.129.
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.
对促成骨关节炎的异常新生血管形成的不完全理解表明，仍有待确定其他调节因子。我们的目标是确定富含亮氨酸的α-2-糖蛋白1（LRG1）（一种致病性血管生成的新调节因子）在骨关节炎进展中的作用，并制定有效的治疗策略。在本研究中，免疫组织化学显示，在交叉韧带切断术（ACLT）小鼠的软骨下骨和关节软骨中，LRG1增加。进一步的研究集中在LRG1在骨关节炎中的作用。结果显示，LRG1促进血管生成和间充质干细胞（MSC）迁移，这有助于软骨下骨中异常的骨形成。此外，肿瘤坏死因子-α（TNF-α）而非白细胞介素-1β（IL-1β）、IL-6或IL-17诱导人脐静脉内皮细胞中LRG1的表达，并且这种作用被p38丝裂原活化蛋白激酶或NF-κB抑制剂抑制。值得注意的是，在ACLT小鼠中，通过来那度胺（一种TNF-α产生抑制剂）抑制TNF-α和LRG1活性可减轻骨关节炎关节软骨的退变。本研究表明，TNF-α是诱导LRG1分泌的主要促炎细胞因子。LRG1通过增加血管生成和在骨关节炎关节的软骨下骨中募集间充质干细胞，促进血管生成耦联的新生骨形成。来那度胺抑制TNF-α和LRG1可能是一种潜在的治疗方法。
