Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis

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.

Structure and function of the mammalian fibrillin gene family: Implications for human connective tissue diseases

“…Progenitor connective tissue cells can be further differentiated into specialized cell types through multiple lineage pathways leading to, for example, adipocytes, chondrocytes, myocytes, osteoblasts and fibroblasts. Cells of these lineages are also involved in connective tissue repair and are the major cellular component in scarring and fibrosis [2,3].…”

Gene polymorphisms of fibronectin rs2289202 and fibrillin 2 rs331069 associate with vascular disease, the TAMRISK study

“…However, there was no association of this variation with cerebrovascular disease as such. The fibrillins FBN1 and FBN2 polymerize to a scaffold for the assembly of elastin that provides architectural framework for tissues (14). Fibrillin is present in blood vessels to convey elasticity and flexibility to resist stretch and pressure forces.…”

C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43

“…Various mouse models have been created to study the role of fibrillins in tissue homeostasis and disease pathology (27,28), however whole organism models do not provide a molecular understanding of the microfibril assembly process. Additionally, some simpler model organisms such Drosophila melanogaster and Caenorhabditis elegans, do not have fibrillin homologs (8).…”