Interactions entre la Fibrilline-1 et le TGF-β

Conséquences en pathologie humaine

FBN-1/TGF-β relationships and fibrillopathies

¹ Inserm U781, Université Paris Descartes, Hôpital Necker, 149, rue de Sèvres, 75015 Paris, France.
¹ Service de Rhumatologie A, Université Paris Descartes, Hôpital Cochin, AP-HP, 27, rue du Faubourg Saint Jacques, 75014 Paris, France
² Laboratoire de Biochimie, d’Hormonologie et de Génétique Moléculaire, UVSQ, Hôpital Ambroise Paré, 92100 Boulogne-Billancourt, France

^* julien.wipff@cch.aphp.fr

Résumé

La fibrilline-1 (FBN-1) est le principal composant des microfibrilles de la matrice extracellulaire (MEC), soutien architectural des tissus qui participe également à la régulation de différentes cytokines et facteurs de croissance. De nombreux arguments plaident en faveur d’une relation étroite entre la FBN-1 et le TGF-β (transforming growth factor β), prototype des cytokines profibrosantes. Cette interaction pourrait participer à la physiopathologie du syndrome de Marfan et de la sclérodermie systémique. Mieux comprendre les relations entre la FBN-1 et le TGF-β est ainsi un enjeu primordial dans les pathologies matricielles. Cela pourrait conduire à repenser le cadre nosologique de celles-ci en les intégrant dans les « signalopathies » TGF-β. Cette nouvelle approche pourrrait ouvrir des perspectives thérapeutiques innovantes.

Abstract

Fibrillin-1 (FBN-1) is the main component of the 10-12 nm microfibrils found in the extracellular matrix (ECM). ECM dysplays a structural role in the tissue-specific organization and takes part in the regulation of various cytokines and growth factors. A growing body of evidences supports a narrow relationship between FBN-1 and TGF-β. Homology between FBN-1 and latent TGF-β (LTGF) allows microfibrills to be a reservoir for this cytokine. The Marfan syndrome (MFS), a prototypic fibrillinopathy, highlights these relationships as it relates to 2 major genes that are FBN1 and TGF-β type II receptor (TGFBR2) genes. In a mouse model of MFS, an up-regulation of the TGF-β pathway is partly responsible for the phenotype. This FBN-1/TGF-β relationship may play also a role in systemic sclerosis (SSc), a multigenic disease characterized by excessive generalised ECM deposit. Indeed, two related animal models results from both gene mutations: the Tight Skin 1 mouse is due to a partial in-frame duplication of the Fbn1 gene and another model conditionally overexpresses TGF-β type I receptor. A better understanding of FBN-1/TGF-β relationship appears of great importance in fibrillinopathies: it may allow reconsidering the nosologic framework of these diseases including the TGF-β signalopathies and could lead to innovative therapeutic strategies.