Fibroblast-derived MMP-14 regulates collagen homeostasis in adult skin

Zigrino P, Brinckmann J, Niehoff A, Lu Y, Giebeler N, Eckes B, Kadler KE, Mauch C

J. Invest. Dermatol. 2016 Apr;

PMID: 27066886

Abstract

Proteolytic activities in the extracellular matrix by the MMP-14 have been implicated in the remodeling of collagenous proteins during development. To analyze the function of fibroblast-derived MMP-14 in adult skin homeostasis we generated mice with inducible deletion of MMP-14 in the dermal fibroblast (MMP-14(Sf-/-)). These mice are smaller and display a fibrosis-like phenotype in skin. The skin of these mice showed increased stiffness and tensile strength, but no altered collagen cross-links. In vivo, we measured a significantly increased amount of collagen type I accumulated in the skin of MMP-14(Sf-/-) without an increase in collagen fibrils diameters. However, bleomycin-induced fibrosis in skin proceeded in a comparable manner in MMP-14(Sf+/+) and MMP-14(Sf-/-), but resolution overtime was impaired in MMP-14(Sf-/-.). Increased accumulation of collagen type I was detected in MMP-14(Sf-/-) fibroblasts in culture without significant enhancement of collagen de novo synthesis. This points to a degradative, but not synthetic phenotype. In support of this, MMP-14(Sf-/-) fibroblasts lost their ability to process fibrillar collagen type I and to activate proMMP-2. Taken together, these data indicate that MMP-14 expression in fibroblasts plays a crucial role in collagen remodeling in adult skin and largely contributes to dermal homeostasis underlying its pathogenic role in fibrotic skin disease.

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