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Ribosomal S6 Protein Kinase 2 Aggravates the Process of Systemic Scleroderma

      Systemic sclerosis is a complex process of pathogenesis, and the contributions of inherited genes, infections, and chemicals remain largely unknown. In this study, we showed that p90 ribosomal S6 protein kinase 2 (RSK2) was selectively upregulated in fibrotic skin and fibroblasts treated with the profibrotic cytokine TGF-β. Moreover, knockout of Rsk2 specifically in skin fibroblasts or pharmacological inhibition of RSK2 attenuated skin fibrosis in a mouse model. Mechanistically, RSK2 directly interacted with glycogen synthase kinase 3β in vivo and in vitro and thereby induced phosphorylation of glycogen synthase kinase 3β 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 systemic sclerosis. These findings provided a potential therapeutic target for systemic sclerosis.

      Graphical abstract

      Abbreviations:

      α-SMA (α-smooth muscle actin), BLM (bleomycin), ECM (extracellular matrix), HDF (human primary dermal fibroblast), Hh (hedgehog), RSK2 (p90 ribosomal S6 kinase 2), siRSK2 (p90 ribosomal S6 kinase 2‒targeting small interfering RNA), SSc (systemic sclerosis), TBR (TGFβ receptor I)
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