Excessive expression of type I collagen in systemic and localized scleroderma is caused by the down-regulation of microRNA let-7a

Abstract

Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Little is known about the exact mechanism which mediates excessive collagen expression in these cutaneous fibrotic disorders. In the present study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in these diseases.First, to determine which microRNAs are involved in the pathogenesis of skin fibrosis, we performed microRNA PCR array analysis, and the microRNA expression profile in the involved skin of SSc and LSc was compared with that of normal skin. We focused on let-7a, one of the down-regulated microRNAs in SSc and LSc. We demonstrated let-7a expression was down-regulated in SSc and LSc fibroblasts both in vivo and in vitro, compared with normal or keloidal fibroblasts by real-time PCR and in situ hybridization. The forced down-regulation of let-7a in dermal fibroblasts led to the overexpression of type I collagen. Next, we purified microRNA from serum and investigated serum let-7a levels in patients with LSc or SSc. let-7a concentration was decreased in these patients, correlating with the disease activity. Moreover, we demonstrated that the let-7a levels in mice back skin were significantly increased by the intraperitoneal injection of atelocollagen and let-7a mixture, and the intermittent overexpression of let-7a by the injection attenuated bleomycin-induced mouse skin fibrosis.Investigation of more detailed mechanisms of microRNA-mediated regulation of collagen expression may lead to new therapeutic approach against cutaneous fibrosis using microRNA. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF