Pro-fibrotic phenotype of human skin fibroblasts induced by periostin via modulating TGF-β signaling.

BACKGROUND: Periostin is a matricellular protein that belongs to a class of extracellular matrix (ECM)-related molecules defined by their ability to modulate cell-matrix interactions. We previously reported an elevated level of circulating periostin in patients with systemic sclerosis (SSc) and its association with the severity of skin sclerosis.
OBJECTIVE: To examine the role of periostin in transforming growth factor (TGF)-β signaling involved in fibrosis.
METHODS: Levels of periostin were examined in skin and lung fibroblasts obtained from SSc patients. Levels of ECM proteins and pro-fibrotic factors were evaluated in periostin-expressing human skin fibroblasts in the presence or absence of TGF-β. Effects of periostin on the Smad proteins were also evaluated following stimulation with TGF-β by immunoblotting, immunofluorescence staining, and RNA interference.
RESULTS: Periostin was strongly expressed in skin and lung fibroblasts from SSc patients. Although recombinant periostin alone did not affect ECM protein levels, TGF-β and recombinant periostin treatment or periostin overexpression in skin fibroblasts significantly enhanced the production of ECM proteins. Overexpression of periostin in the presence of TGF-β also augmented expressions of α-smooth muscle actin and early growth response-1 but decreased the level and activity of matrix metalloproteinase 1. Interestingly, the level of Smad 7, a TGF-β-inducible inhibitor of TGF-β signaling, was reduced in periostin-expressing fibroblasts but increased in periostin-silenced fibroblasts. In addition, Smad 7 reduction induced by periostin was partially inhibited in integrin αV-silenced fibroblasts.
CONCLUSION: Periostin contributes to fibrosis by enhancing TGF-β signaling via Smad 7 inhibition, which may lead to ECM deposition and periostin generation.