Center of Joint Surgery and Sports Medicine, Department of Orthopedics, Changzheng Hospital, Second Military Medical University, China.
Department of Orthopedics, Wanzai County People's Hospital, China.
Biochem Biophys Res Commun. 2019 Jun 25;514(2):482-489. doi: 10.1016/j.bbrc.2019.04.163. Epub 2019 May 2.
Traditionally, the development of osteoarthritis (OA) is associated with factors such as aging and injure, but more and more epidemiological and biological evidence suggests that the disease is closely related to metabolic syndrome and metabolic components. Ubiquitin-specific protease 3(USP3), a member of the USPs family, is a specific protease capable of cleavage of ubiquitin chains linked by proline residues. In our presented study, we firstly found that USP3 expression level was decreased in OA. USP3 overexpression inhibited IL-1β induced chondrocytes apoptosis and nuclear factor κB (NF-κB) activation. USP3 knockdown induced chondrocytes apoptosis and activated NF-κB pathway. USP3 interacts with TRAF6 (tumor necrosis factor-receptor-associated factor 6), which is an essential adaptor protein for the NF-κB (nuclear factor κB) signaling pathway and plays important roles in inflammation and immune response. IL-1β treatment up-regulated the polyubiquitination of TRAF6 in chondrocytes, which was attenuated when USP3 was forced expression. Our study mechanistically links USP3 to TRAF6 in osteoarthritis development. Moreover, these data support the pursuit of USP3 and TRAF6 as potential targets for osteoarthritis therapies.
传统上，骨关节炎（OA）的发展与衰老和损伤等因素有关，但越来越多的流行病学和生物学证据表明，该疾病与代谢综合征和代谢成分密切相关。泛素特异性蛋白酶 3（USP3）是 USP 家族的成员，是一种能够切割脯氨酸残基连接的泛素链的特异性蛋白酶。在我们目前的研究中，我们首先发现 USP3 在 OA 中的表达水平降低。USP3 过表达抑制了 IL-1β 诱导的软骨细胞凋亡和核因子 κB（NF-κB）激活。USP3 敲低诱导软骨细胞凋亡并激活 NF-κB 通路。USP3 与 TRAF6（肿瘤坏死因子受体相关因子 6）相互作用，TRAF6 是 NF-κB（核因子 κB）信号通路的必需衔接蛋白，在炎症和免疫反应中发挥重要作用。IL-1β 处理上调了软骨细胞中 TRAF6 的多泛素化，当 USP3 被强制表达时，这种多泛素化被减弱。我们的研究从机制上把 USP3 与 TRAF6 联系起来，从而促进了骨关节炎的发展。此外，这些数据支持将 USP3 和 TRAF6 作为骨关节炎治疗的潜在靶点进行研究。
