FGF21 Ameliorates Fibroblasts Activation and Systemic Sclerosis by Inhibiting CK2α/GLI2 Signaling Axis

Systemic sclerosis (SSc) is a typical fibrotic disease of unknown etiology, which is characterized by abnormal fibroblast activation and excessive deposition of extracellular matrix. Unfortunately, effective therapeutic approaches are lacking. Fibroblast growth factor 21 (FGF21) plays a key role in mediating a variety of biological activities. However, its specific function in SSc is unclear. In this study, we found that the expression of FGF21 was significantly downregulated in fibrotic skin tissue and in transforming growth factor-β (TGF-β) stimulated fibroblasts. Furthermore, our studies demonstrated that treatment with recombinant FGF21 in the skin significantly alleviated bleomycin (BLM)-induced and TGF-β receptor I (TBRI)-activated fibrosis and inhibited the activation of fibroblasts, while skin fibrosis was exacerbated by deletion of FGF21. Mechanistically, FGF21 inhibits the activity of CK2α and promotes the degradation of GLI2. In conclusion, these results indicate that FGF21 attenuates skin fibrosis via the CK2α/GLI2 signaling pathway and therefore may be a potential therapeutic target for systemic sclerosis.