Roles of short fibulins, a family of matricellular proteins, in lung matrix assembly and disease

Abstract

Cyclical inflation of the lungs depends on the elasticity of lung parenchymal tissues, a mechanical property that is largely determined by elastic fibers and collagen fibers contained therein. Breakdown of elastic fibers in lungs and lack of the ability to repair damaged elastic fibers causes emphysema, and excessive collagen fibrillogenesis in lung parenchyma is critical for the pathogenesis of lung fibrosis. Recent studies revealed that fibulin-3, 4, and 5, which are matricellular proteins collectively termed “short fibulins” or “elastic fibulins”, play crucial roles in the assembly of elastic fibers. Although these fibulins are closely related paralogs with very similar domain structures and sequences, they have independent molecular functions in elastogenesis, as evidenced by different phenotypes in their gene-knockout mice and in patients with mutations in these genes. More recently, emerging evidence suggests that fibulin-4 is also necessary for fibrillar collagen assembly. In this review, I focus on the roles of short fibulins and their associating molecules in the assembly of elastic fibers and collagen fibers. Human diseases caused by mutations in the genes for these molecules are also reviewed. These matricellular proteins could be novel therapeutic targets for emphysema and lung fibrosis.