Suppressive regulation of MFG-E8 on latent-TGF-β-induced fibrosis via binding to integrin αV: The significance in the pathogenesis of fibrosis in systemic sclerosis.

OBJECTIVE: Several studies have demonstrated that secreted glycoprotein and integrin ligand MFG-E8 negatively regulate fibrosis in the liver, lungs and respiratory tract. However, the mechanisms and roles of MFG-E8 in skin fibrosis in systemic sclerosis (SSc) have not been characterized. This study aimed to elucidate the role of MFG-E8 in skin fibrosis in SSc.

METHODS: The expression of MFG-E8 in the skin and serum in SSc patients was assessed. The effect of rMFG-E8 on latent-TGF-β-induced gene/protein expression in SSc fibroblasts was examined. The effects of deficiency or administration of MFG-E8 on fibrosis mouse models were examined.

RESULTS: We demonstrated that MFG-E8 expression around the dermal blood vessels and the serum MFG-E8 level in SSc patients were lower than those in healthy individuals. Treatment with rMFG-E8 significantly inhibited latent-TGF-β-induced collagen type I, αSMA and CCN2 expression in SSc fibroblasts, suggesting that MFG-E8 inhibited the activation of latent-TGF-β as well as TGF-β signaling via binding to integrin αV. In a bleomycin-induced fibrosis mouse model and tight-skin mouse, a genetic model of SSc, deficient expression of MFG-E8 significantly enhanced both pulmonary and skin fibrosis, and administration of rMFG-E8 significantly inhibited bleomycin-induced dermal fibrosis.

CONCLUSIONS: These results suggest that vasculopathy-induced dysfunction of pericytes and endothelial cells, the main secretory cells of MFG-E8, may be associated with the decreased expression of MFG-E8 in SSc and that the deficient inhibitory regulation of latent-TGF-β-induced skin fibrosis by MFG-E8 may be involved in the pathogenesis of SSc and may be a therapeutic target for fibrosis in SSc patients. This article is protected by copyright. All rights reserved.