The Fibrillinopathies: Fibrillin-Dependent Skeletal Dysplasias Affecting Long Bone Growth

Fibrillin-1 and -2 form supramolecular networks in the connective tissue space that are crucial for development and homeostasis of bone tissues. These so called fibrillin microfibrils with their associated ligands form an intricate cellular microenvironment that controls cellular behavior of bone resident cells. This is illustrated by the skeletal features of congenital connective disorders caused by FBN1 or FBN2 mutations that are characterized by long bone over- or undergrowth and are collectively termed as fibrillinopathies. The skeletal features of the fibrillinopathies suggest an involvement of both fibrillins in the regulation of growth and differentiation processes of bone tissues; however, a clear understanding of how fibrillins control cellular processes of bone resident cells is still lacking. Fibrillins were shown to target and sequester growth factors of the TGF-β superfamily, but how they control growth factor bioavailability and thereby fine tune signal transduction requires further investigation. However, several studies employing biochemical experiments on the molecular protein level and Fbn1 knock-in mouse models have provided new insightful mechanistic information, over the last years. Here, we will give an overview about the current concepts of how fibrillin deficiency impacts bone physiology and how this information may be utilized to explore new therapeutic avenues for patients with skeletal dysplasias due to fibrillin deficiency.