Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies

Abstract

The fibulin family of extracellular matrix/matricellular proteins is composed of long fibulins (fibulin-1, -2, -6) and short fibulins (fibulin-3, -4, -5, -7) and is involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. Fibulin-1, -2, -3, -4, and -5 bind the monomeric form of elastin (tropoelastin) in vitro and fibulin-2, -3, -4, and -5 are shown to be involved in various aspects of elastic fiber development in vivo. In particular, fibulin-4 and -5 are critical molecules for elastic fiber assembly and play a non-redundant role during elastic fiber formation. Despite manifestation of systemic elastic fiber defects in all elastogenic tissues, fibulin-5 null (Fbln5(-/-)) mice have a normal lifespan. In contrast, fibulin-4 null (Fbln4(-/-)) mice die during the perinatal period due to rupture of aortic aneurysms, indicating differential functions of fibulin-4 and fibulin-5 in normal development. In this review, we will update biochemical characterization of fibulin-4 and fibulin-5 and discuss their roles in elastogenesis and outside of elastogenesis based on knowledge obtained from loss-of-function studies in mouse and in human patients with FBLN4 or FBLN5 mutations. Finally, we will evaluate therapeutic options for matrix-related diseases.

Keywords: Aortic aneurysm; Collagen fibers; Cutis laxa; ECM; Elastic fibers; Integrin.

Fig. 1. Schematic presentation of fibulins-4 and -5

Fibulin-4 and fibulin-5 are shown with known interacting proteins involved in elastic fiber assembly. Red and blue lines indicate interacting domain(s) for fibulin-4 and fibulin-5, respectively, determined by solid-phase binding assays, BIAcore, or Co-IP. The line encompassing an entire sequence indicates that the binding domain(s) have not been determined.

Fig. 2. Proposed functions of fibulins-4 and -5 during elastogenesis

Elastic fibers are divided into elastin core (gray) and microfibril scaffold (green). Each step of elastogenesis is shown on the left and molecular interactions among components of elastic fibers and potential functions of fibulins are indicated by arrows.