Dyrk1A promotes the proliferation, migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis via down-regulating Spry2 and activating the ERK MAPK pathway

摘要

Fibroblast-like synoviocytes (FLSs) play an essential role in rheumatoid arthritis (RA) by promoting synovitis, pannus growth and cartilage/bone destruction. Increased proliferation, migration and invasion of FLSs greatly contribute to RA initiation and progression. Dual-specificity tyrosine-regulated kinase 1A (Dyrk1A), a serine/threonine kinase, regulates MAPK pathway activation, and governs the proliferation and differentiation of neuronal progenitor cells and cancer cells. Till now, the expression and possible function of Dyrk1A in RA FLSs have not been explored. In this study, we detected an increased expression of Dyrk1A both in the synovial tissues of RA patients and in a TNF-alpha-induced FLSs activation model. CCK-8 and Edu assays revealed that Dyrk1A knockdown inhibited TNF-alpha-induced FLSs proliferation. Moreover, inhibiting Dyrk1A expression apparently prevented the migration and invasion capability of FLSs accompanied by a decreased MMP-3 and -9 expression. To investigate the molecular mechanism through which Dyrk1A modulates FLSs activities, we evaluated the effects of Dyrk1 A on Spry2, a negativity modulator of ERK MAPK pathway. Western blot assay demonstrated that Dyrk1A silencing significantly increased Spry2 expression and suppressed the phosphorylation of ERK in TNF-alpha-treated FLSs. Taken together, our results indicated that Dyrk1A might promote FLSs proliferation, migration and invasion by suppressing Spry2 expression and activating the ERK MAPK signaling pathway in RA.