JOSD2 attenuates the aggressive behavior of fibroblast-like synoviocytes in rheumatoid arthritis by deubiquitinating and stabilizing ZNF148.

BACKGROUND: Activated fibroblast-like synoviocytes (FLS) significantly promote synovial inflammation and bone destruction in rheumatoid arthritis (RA). Emerging evidence illustrates that ubiquitination significantly drives both inflammatory processes and the regulation of immunity. This study aimed to elucidate the role of the deubiquitinase Josephin domain-containing protein 2 (JOSD2) in RA-FLS. METHODS: Quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry were used to detect the expression of JOSD2 in the RA-FLS cell line MH7A. Cell migration and invasion were assessed using wound-healing assays and Transwell invasion assays, respectively. qRT-PCR was conducted to evaluate the expression of cytokines and matrix metalloproteinases (MMPs). Potential interacting proteins of JOSD2 were screened by mass spectrometry analysis. Ubiquitination assays were conducted to examine the ubiquitination level of zinc finger protein 148 (ZNF148). A collagen-induced arthritis (CIA) mouse model was established to evaluate the therapeutic effect of JOSD2. RESULTS: JOSD2 expression was decreased in MH7A cells and synovial tissue. Overexpression of JOSD2 attenuated the migration and invasion of MH7A cells, as well as the expression of IL-6, IL-1β, MMP1, MMP3, and MMP9, whereas JOSD2 knockdown exhibited opposite effects. Mechanistically, JOSD2 maintained ZNF148 stability by removing K48-linked ubiquitin chains. Overexpression of ZNF148 alleviated migration, invasion, and the inflammatory response of MH7A cells. Furthermore, intra-articular overexpression of JOSD2 alleviated synovial inflammation and bone destruction in CIA mice. CONCLUSION: Our results highlight that increased JOSD2 attenuates the aggressive behaviors of RA-FLS and alleviates synovial inflammation. The JOSD2-ZNF148 axis may represent a potential therapeutic strategy for RA.