Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Elastogenesis is a complex biological process that involves the organized deposition and self-assembly of several macromolecules into microfibrils and elastic fibers (1). Elastic fibers are made of an amorphous core of cross-linked elastin and other molecules and microfibrils; the latter are heterogeneous in composition and can also form macroaggregates devoid of elastin (2, 3). Fibrillins 1 and 2 are the main structural components of extracellular microfibrils and the defective gene products in Marfan syndrome (MFS) 3 and congenital contractural arachnodactyly (CCA), respectively (4, 5). MFS is a pleiotropic disorder of the connective tissue with wide variation in clinical severity (6). Cardiovascular manifestations in the form of aortic dilatation, dissection, and rupture contribute significantly to morbidity and mortality in affected individuals. CCA, on the other hand, is a rare condition akin to MFS but with major manifestations confined to the musculoskeletal system (6). Fibrillins are large cysteine-rich glycoproteins (ϳ350 kDa) composed primarily of multiple repeated domains homologous to the calcium binding epidermal growth factor module and of distinct 8-cysteine modules (2, 3, 5). Fibrillins polymerize into a characteristic beadson-a-string microfibril structure, which gives rise to the microfibril lattice by lateral association of the individual microfibril polymers and probable association of other structural components. Fibrillins can form homo-or heteropolymeric microfibrils and can interact with integrins, growth factors, several other matrix components, and latent transforming growth factor ␤-binding proteins.Differential expression of elastic fiber components, dynamic cell-matrix interactions, and microfibril-mediated modulation of signaling molecules account for the diverse architectures and functions of elastic networks during the development and growth of individual organ systems (5). The process of aortic media formation is an illustrative example of the interplay between resident cells and elastic fiber components that ultimately results in the highly organized and functionally competent tissue (7,8). At about mid-gestation, vascular smooth muscle cells (VSMC) deposit fibrillins and tropoelastin molecules into the surrounding matrix and begin to organize them into elastic fibers. The latter process extends into early neonatal life accompanied by the gradual growth of elastic fibers into mature elastic lamellae that separate parallel layers of quiescent VSMC. The resulting organization of th...

Latent transforming growth factor (TGF)␤Results demonstrate that these protein-protein interactions exhibit "exquisite specificities," a phrase commonly used to describe monoclonal antibody interactions. Despite these differences, interactions between LTBP-1 and fibrillin-1 compete for interactions between fibrillin-1 and these fibulins. All of these proteins have been immunolocalized to microfibrils. However, in fibrillin-1 (Fbn1) null fibroblast cultures, LTBP-1 and LTBP-4 are not incorporated into microfibrils. In contrast, in fibulin-2 (Fbln2) null or fibulin-4 (Fbln4) null cultures, fibrillin-1, LTBP-1, and LTBP-4 are incorporated into microfibrils. These data show for the first time that fibrillin-1, but not fibulin-2 or fibulin-4, is required for appropriate matrix assembly of LTBPs. These studies also suggest that the fibulins may affect matrix sequestration of LTBPs, because in vitro interactions between these proteins are competitive.

Extracellular microfibrils composed of fibrillin-1 and -2 regulate bone formation through modulation of TGF-β and BMP signaling.