Supernatants from culture of type I collagen-stimulated PBMC from patients with cutaneous systemic sclerosis versus localized scleroderma demonstrate suppression of MMP-1 by fibroblasts

Monica Brown,Linda K Myers,Arnold E Postlethwaite,Karen A Hasty

doi:10.1007/s10067-012-1962-z

Abstract

Systemic sclerosis (SSc) is a chronic fibrosing disease characterized by vasculopathy, autoimmunity, and an accumulation of collagen in tissues. Numerous studies have shown that compared to healthy or diseased controls, the peripheral blood mononuclear cells (PBMC) from patients with SSc produce a variety of cytokines or proliferate when cultured with solubilized type I collagen (CI) or constituent α1(II) and α2(I) polypeptide chains. The purpose of this study was to determine whether PBMC isolated from patients with SSc and cultured in vitro with soluble CI elaborated soluble mediators that inhibit the production of collagenase (i.e., matrix metalloproteinase, MMP-1) by fibroblasts. Supernatants of CI-stimulated PBMC from juvenile and adult diffuse cutaneous (dc)SSc patients significantly reduced MMP-1 production by SSc dermal fibroblasts, while supernatants of CI-stimulated PBMC from patients with localized scleroderma (LS) did not. CI-stimulated PBMC culture supernatants from patients with dcSSc in contrast to patients with LS exhibited increased levels of platelet-derived growth factor (PDGF)-AA, PDGF-BB, TNF-α, IL-13, and EGF. Prolonged culture of SSc dermal fibroblasts with recombinant PDGF-BB or IL-13 inhibited the induction of MMP-1 in response to subsequent TNF-α stimulation. These data suggest that therapies aimed at reducing these cytokines may decrease collagen accumulation in SSc, preventing the development of chronic fibrosis.

Highlights

Scleroderma “fibrosis of the skin” spectrum disorders include localized scleroderma (LS) variants and systemic sclerosis (SSc) the latter of which is further divided into diffuse cutaneousSSc, limited cutaneous SSc, and SSc sine scleroderma
We found that long-term exposure to supernatants that had been generated by culturing CI-stimulated peripheral blood mononuclear cells (PBMC) from adult or pediatric patients with dcSSc caused a significant decrease in the production of matrix metalloproteinase (MMP)-1 by SSc fibroblasts
Inhibition of MMP-1 production by dcSSc dermal fibroblasts chronically exposed in vitro to pooled culture supernatants from CI-stimulated PBMC from patients with dcSSc To determine whether cytokine/growth factors present in supernatants from culture of CI-stimulated SSc PBMC would effect a change in MMP-1 production by dermal fibroblasts, we obtained PBMC from ten adult patients with dcSSc and Cytokine profile for CI-stimulated PBMC supernatants from juvenile and adult dcSSc The inhibition of MMP-1 described above is very likely induced by cytokines or growth factors secreted by peripheral blood cells

Summary

Introduction

Scleroderma “fibrosis of the skin” spectrum disorders include localized scleroderma (LS) variants and systemic sclerosis (SSc) the latter of which is further divided into diffuse cutaneous (dc)SSc, limited cutaneous (lc) SSc, and SSc sine scleroderma. The forms of SSc are differentiated primarily on the basis of the pattern of skin involvement, autoantibody association, and characteristics of internal organ involvement [1]. Five subtypes of LS or morphea are recognized by Peterson et al and include “plaque,” “generalized,” “bullous,” “linear,” and “deep” [2]. Clin Rheumatol (2012) 31:973–981 subgroups and recognizes “mixed variant morphea” which includes a combination of two or more subtypes in the same patient. Antinuclear antibodies are present in only 20% to 80% of patients with LS and in >90% of patients with SSc [4, 5]. Antitopoisomerase II alpha antibody is present in up to 85% of patients with LS and in 14% of patients with SSc [4]

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