Involvement of αvβ5 Integrin in the Establishment of Autocrine TGF-β Signaling in Dermal Fibroblasts Derived from Localized Scleroderma

Abstract

Localized scleroderma (LSc) is a connective tissue disorder limited to skin and subcutaneous tissue, which may share pathogenic processes with systemic sclerosis (SSc). We previously demonstrated that upregulated expression of integrin alphavbeta5 might contribute to autocrine TGF-beta signaling in SSc fibroblasts. Based on these data, we presently focused on alphavbeta5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-beta. Consistent with SSc fibroblasts, expression levels of alphavbeta5 were elevated in LSc fibroblasts in vitro and in vivo. Anti-alphavbeta5 antibody partially reversed expression levels of type I procollagen and MMP-1 and constitutive DNA-Smad3 binding in LSc fibroblasts. In LSc fibroblasts pretreated with antisense TGF-beta1, exogenous latent TGF-beta1 stimulation increased expression of type I procollagen in an alphavbeta5-dependent manner. The luciferase activities of TMLC cells, Mv1Lu cells stably expressing a portion of the plasminogen activator inhibitor 1 promoter, co-cultured with LSc fibroblasts were significantly elevated compared with those co-cultured with normal fibroblasts and were significantly reduced in the presence of anti-alphavbeta5 antibody. Anti-alphavbeta5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of alphavbeta5 contributes to autocrine TGF-beta signaling in LSc fibroblasts.

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

“…These results extend the traction model developed for avb6, and are consistent with data that fibroblasts from dermis affected by localized scleroderma, but not from normal dermis, activate TGF-b in an avb5-dependent manner (Asano et al 2006). It appears that ECM, mesenchymal cells and TGF-b have selfreinforcing interactions in wound healing.…”

The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma

“…As described in previous reports (11,36), the expression of both a1(I) and a2(I) chain, two major components of type I collagen, was significantly increased in SSc ( Fig. 2A) and LSc (Fig.…”

“…Localized scleroderma (LSc) also manifests tissue fibrosis limited to the skin and s.c. tissue, occasionally involving the muscular tissues beneath the cutaneous lesions (1,2), but the presence of Raynaud's phenomenon, acrosclerosis, and involvement of internal organs differentiates SSc from LSc (3). Abnormal collagen metabolism (4)(5)(6)(7)(8) and autoimmunity (9,10) are considered to be fundamental common characteristics of SSc and LSc, and especially, excess collagen production by dermal fibroblasts is thought to be caused by intrinsic activation of TGF-b signaling in both diseases (5,11).…”

Autoantibodies against matrix metalloproteinase-1 in patients with localized scleroderma

“…In SSc, a previous study has shown that SSc fibroblasts exhibit decrease in MMP-1 activity and production compared with normal fibroblasts [19]. Likewise, decrease in MMP-1 expression is observed in the LSc fibroblasts [20]. Moreover, the efficacy of ultraviolet A phototherapy on skin fibrosis is mainly obtained by increased production of MMP-1 and interferon-γ in LSc [21].…”