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

• Fibulin-4 and -5 bind elastin and are essential for development of elastic fibers.
• Mutations in FBLN4 or FBLN5 gene cause autosomal recessive cutis laxa.
• Smooth muscle cell-derived fibulin-4 is crucial for preventing ascending aortic aneurysm.
• Fibulin-5 regulates protease activities in an integrin dependent manner.
• Anti-miR29-b therapy may be useful for subsets of ECM-related diseases.

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.