Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis.

Jacopo Olivieri,Silvia Smaldone,Francesco Ramirez

doi:10.1186/1755-1536-3-24

Abstract

The extracellular matrix (ECM) plays a key role in tissue formation, homeostasis and repair, mutations in ECM components have catastrophic consequences for organ function and therefore, for the fitness and survival of the organism. Collagen, fibrillin and elastin polymers represent the architectural scaffolds that impart specific mechanic properties to tissues and organs. Fibrillin assemblies (microfibrils) have the additional function of distributing, concentrating and modulating local transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signals that regulate a plethora of cellular activities, including ECM formation and remodeling. Fibrillins also contain binding sites for integrin receptors, which induce adaptive responses to changes in the extracellular microenvironment by reorganizing the cytoskeleton, controlling gene expression, and releasing and activating matrix-bound latent TGF-β complexes. Genetic evidence has indicated that fibrillin-1 and fibrillin-2 contribute differently to the organization and structural properties of non-collagenous architectural scaffolds, which in turn translate into discrete regulatory outcomes of locally released TGF-β and BMP signals. Additionally, the study of congenital dysfunctions of fibrillin-1 has yielded insights into the pathogenesis of acquired connective tissue disorders of the connective tissue, such as scleroderma. On the one hand, mutations that affect the structure or expression of fibrillin-1 perturb microfibril biogenesis, stimulate improper latent TGF-β activation, and give rise to the pleiotropic manifestations in Marfan syndrome (MFS). On the other hand, mutations located around the integrin-binding site of fibrillin-1 perturb cell matrix interactions, architectural matrix assembly and extracellular distribution of latent TGF-β complexes, and lead to the highly restricted fibrotic phenotype of Stiff Skin syndrome. Understanding the molecular similarities and differences between congenital and acquired forms of skin fibrosis may therefore provide new therapeutic tools to mitigate or even prevent disease progression in scleroderma and perhaps other fibrotic conditions.

Highlights

The extracellular matrix (ECM) is a highly heterogeneous amalgam of morphologically diverse architectural entities composed of collagenous or elastic polymers, adaptor proteins and hydrophilic proteoglycans
The strategy was based on the prior knowledge that blockade of angiotensin II receptor I (AT1R) activity reduces excessive transforming growth factor (TGF)-b signaling in experimental renal and cardiac fibrosis [94,95]. within accordance with this prediction, losartan treatment was shown to restore aortic wall architecture in Fbn1C1039G/+ mice and to mitigate aortic root dilation in a small cohort of children with severe Marfan syndrome (MFS) [46,96]
A more recent study has confirmed the efficacy of losartan treatment in improving aortic wall degeneration in Fbn1mgR/mgR mice, a more severe model of MFS than the Fbn1C1039G/+ mouse, even though the regimen showed no beneficial impact to counteract bone loss [49]

Summary

Introduction

The extracellular matrix (ECM) is a highly heterogeneous amalgam of morphologically diverse architectural entities composed of collagenous or elastic polymers, adaptor proteins and hydrophilic proteoglycans. Fibroblasts explanted from involved sites show a transiently activated phenotype characterized by elevated expression of ECM components, MMP inhibitors (TIMPs) and adhesion molecules, in addition to constitutive TGF-b signaling [51] Consistent with this last finding, SSc biopsies display increased activation of the Smad2/3 pathway, and skin fibrosis is observed in transgenic mice overexpressing constitutively active TGFBR1 [61,62]. The larger size of fibrillin-1 together with duplicated RGD sequences may trigger the same cascade of events in the skin of Tsk/+ mice, in addition to eventuating MFS-like manifestations in other organ systems by mechanism(s) that influence other aspects of fibrillin-1 assembly and function [43,91,92] In line with this argument, the pathogenesis of reduced bone mass in Tsk/+ mice differs from that of Fbn1mgR/ mgR mice, as impaired bone formation and increased bone resorption in the latter [49,93]. Further analyses of Tsk/+ mice and creation of SSS mice promises to elucidate the pathogenetic contribution of fibrillin-1 microfibrils to fibrotic phenotypes

Conclusions and perspectives

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