Department of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People's Liberation Army), Xiamen 361003, China.
Department of Orthopedics, Chenggong Hospital of Xiamen University (the 73th Group Military Hospital of People's Liberation Army), Xiamen 361003, China.
Biomed Pharmacother. 2021 Jan;133:111089. doi: 10.1016/j.biopha.2020.111089. Epub 2020 Dec 9.
Osteoarthritis is a chronic, systemic and inflammatory disease. However, the pathogenesis and understanding of RA are still limited. Ubiquitin-specific protease 13 (USP13) belongs to the deubiquitinating enzyme (DUB) superfamily, and has been implicated in various cellular events. Nevertheless, its potential on RA progression has little to be investigated. In the present study, we found that USP13 expression was markedly up-regulated in synovial tissue samples from patients with RA, and was down-regulated in human fibroblast-like synoviocytes (H-FLSs) stimulated by interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). We then showed that over-expressing USP13 markedly suppressed inflammatory response, oxidative stress and apoptosis in H-FLSs upon IL-1β or TNF-α challenge, whereas USP13 knockdown exhibited detrimental effects. In addition, USP13-induced protective effects were associated with the improvement of nuclear factor erythroid 2-related factor 2 (Nrf-2) and the repression of Casapse-3. Furthermore, phosphatase and tensin homolog (PTEN) expression was greatly improved by USP13 in H-FLSs upon IL-1β or TNF-α treatment, whereas phosphorylated AKT expression was diminished. In response to IL-1β or TNF-α exposure, nuclear transcription factor κB (NF-κB) signaling pathway was activated, whereas being significantly restrained in H-FLSs over-expressing USP13. Mechanistically, USP13 directly interacted with PTEN. Of note, we found that USP13-regulated cellular processes including inflammation, oxidative stress and apoptotic cell death were partly dependent on AKT activation. Furthermore, USP13 over-expression effectively inhibited osteoclastogenesis and osteoclast-associated gene expression. The in vivo experiments finally confirmed that USP13 dramatically repressed synovial hyperplasia, inflammatory cell infiltration, cartilage damage and bone loss in collagen-induced arthritis (CIA) mice via the same molecular mechanisms detected in vitro. Taken together, these findings suggested that targeting USP13 may provide feasible therapies for RA.
骨关节炎是一种慢性、全身性和炎症性疾病。然而，RA 的发病机制和理解仍然有限。泛素特异性蛋白酶 13（USP13）属于去泛素化酶（DUB）超家族，已涉及各种细胞事件。然而，其对 RA 进展的潜在作用仍有待研究。在本研究中，我们发现 USP13 表达在 RA 患者的滑膜组织样本中明显上调，并在白细胞介素 1β（IL-1β）、肿瘤坏死因子-α（TNF-α）或脂多糖（LPS）刺激的人成纤维样滑膜细胞（H-FLSs）中下调。然后我们表明，在 IL-1β或 TNF-α 刺激下，过表达 USP13 可显著抑制 H-FLSs 的炎症反应、氧化应激和凋亡，而 USP13 敲低则表现出有害作用。此外，USP13 诱导的保护作用与核因子红细胞 2 相关因子 2（Nrf-2）的改善和 Casapse-3 的抑制有关。此外，在 IL-1β 或 TNF-α 处理的 H-FLSs 中，USP13 大大改善了磷酸酶和张力蛋白同源物（PTEN）的表达，而磷酸化 AKT 的表达则降低。在 IL-1β 或 TNF-α 暴露时，核转录因子 κB（NF-κB）信号通路被激活，而在过表达 USP13 的 H-FLSs 中则被显著抑制。从机制上讲，USP13 直接与 PTEN 相互作用。值得注意的是，我们发现 USP13 调节的细胞过程，包括炎症、氧化应激和凋亡细胞死亡，部分依赖于 AKT 的激活。此外，USP13 过表达可有效抑制破骨细胞生成和破骨细胞相关基因表达。体内实验最终证实，USP13 通过体外检测到的相同分子机制，在胶原诱导关节炎（CIA）小鼠中显著抑制滑膜增生、炎症细胞浸润、软骨损伤和骨丢失。总之，这些发现表明，针对 USP13 可能为 RA 提供可行的治疗方法。
