Fibrosis: Insights from the Stiff Skin syndrome

Abstract

Fibrillin-1 is a 350-kDa glycoprotein component of the extracellular matrix. It is a member of a small family of homologous glycoproteins that includes the fibulins and the latent TGF β-binding proteins (LTBPs). Fibrillin-1 has 43 calciumbinding epidermal growth factor-like (cbEGF-like) domains, 4 noncalcium-binding EGF-like domains, 7 TGF β-binding protein-like (TB) domains, 2 hybrid domains, unique N and C-termini, and a 58-amino-acid proline-rich sequence. Fibrillin-1 is an integral constituent of complex structures in the extracellular matrix called microfibrils [1]. By electron microscopy (EM), microfibrils extracted from tissues or cell culture have a "bead-on-a-string" appearance, with periodically spaced globular domains connected by linear arms [2, 3]. Within the extracellular matrix, microfibrils bind numerous ligands including fibulins, LTBPs, decorin, biglycan, versican, microfibrillar-associated proteins (MAFPs), microfibrilassociated glycoproteins (MAGPs), tropoelastin, heparan sulfate, and some collagens, among others [4]. It is believed that microfibrils form a scaffold for tropoelastin deposition and regulate or inform elastic fiber assembly [5]. Fibrillin-rich microfibrils are found in several elastic and nonelastic tissue types including the skin, vasculature, bones, lungs, and eye.