Ribosomal S6 Protein Kinase 2 Aggravates the Process of Systemic Scleroderma

Abstract

Systemic sclerosis (SSc) is a complex process of pathogenesis, and the contributions of inherited genes, infections, and chemicals remain largely unknown. Here, we demonstrated that p90 ribosomal S6 protein kinase 2 (RSK2) was selectively upregulated in fibrotic skin and fibroblasts treated with the profibrotic cytokine transforming growth factor β (TGF-β). Moreover, knockout of RSK2 specifically in skin fibroblasts or pharmacological inhibition of RSK2 attenuated skin fibrosis in mouse model. Mechanistically, RSK2 directly interacted with glycogen synthase kinase 3β (GSK3β) in vivo and in vitro, and thereby induced phosphorylation of GSK3β at Ser9 to inhibit ubiquitination and degradation of Gli1, which promoted fibroblast differentiation and skin fibrosis. Consequently, RSK2 plays an important role in the dermal skin of SSc. These findings provided a potential therapeutic target for SSc.