Mo Haokun, Yang Siying, Chen An-Min
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biochem Biophys Res Commun. 2022 Oct 20;626:229-235. doi: 10.1016/j.bbrc.2022.08.006. Epub 2022 Aug 12.
Osteoarthritis is a chronic age-related degenerative disease associated with varying degrees of pain and joint mobility disorders. Grb2-associated-Binding protein-2 (GAB2) is an intermediate molecule that plays a role downstream in a variety of signaling pathways, such as inflammatory signaling pathways. The role of GAB2 in the pathogenesis of OA has not been fully studied. In this study, we found that GAB2 expression was elevated in chondrocytes after constructing in vivo and in vitro models of OA. Inhibition of GAB2 by siRNA decreased the expression of MMP3, MMP13, iNOS, COX2, p62, and increased the expression of COL2, SOX9, ATG7, Beclin-1 and LC3II/LC3I. Furthermore, inhibition of GAB2 expression inhibited interleukin-1β (IL-1β) -induced mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling. In vivo studies, we found that reduced GAB2 expression effectively delayed cartilage destruction in a mouse model of OA induced by destabilisation of the medial meniscus (DMM). In conclusion, our study demonstrates that GAB2 is a potential therapeutic target for OA.
骨关节炎是一种与年龄相关的慢性退行性疾病，伴有不同程度的疼痛和关节活动障碍。Grb2相关结合蛋白2（GAB2）是一种中间分子，在多种信号通路（如炎症信号通路）的下游发挥作用。GAB2在骨关节炎发病机制中的作用尚未得到充分研究。在本研究中，我们发现在构建骨关节炎的体内和体外模型后，软骨细胞中GAB2表达升高。通过小干扰RNA抑制GAB2可降低基质金属蛋白酶3（MMP3）、基质金属蛋白酶13（MMP13）、诱导型一氧化氮合酶（iNOS）、环氧化酶2（COX2）、p62的表达，并增加Ⅱ型胶原蛋白（COL2）、性别决定区Y框蛋白9（SOX9）、自噬相关蛋白7（ATG7）、贝林蛋白1（Beclin-1）和微管相关蛋白轻链3Ⅱ型（LC3II）/微管相关蛋白轻链3Ⅰ型（LC3I）的表达。此外，抑制GAB2表达可抑制白细胞介素-1β（IL-1β）诱导的丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号传导。在体内研究中，我们发现降低GAB2表达可有效延缓内侧半月板不稳定（DMM）诱导的骨关节炎小鼠模型中的软骨破坏。总之，我们的研究表明GAB2是骨关节炎的一个潜在治疗靶点。
