Fibulins

Fibulins comprise a group of extracellular matrix proteins or matricellular proteins that are composed of a tandem of an epidermal-growth factor-like domain with a C-terminal fibulin-typical module. The family consists of 7 members, the fibulins-1 to fibulin-7 (de Vega S et al. 2014). For functional and molecular reasons, the fibulin group can be divided into long fibulins, fibulins 1/2/6, and short fibulins, fibulins 3/4/5/7 (Papke CL et al. 2014). Chemically, all fibulins are glycoproteins that are embedded in the fibrillar extracellular matrix of different organ systems in varying densities.

Animal experiments have shown that fibulins bind to tropoelastin. This binding was intense for fibulin-2 and -5, moderate for fibulins 4 and 1, and relatively weak for fibulin-3; fibulin-4, but not fibulins 3 and 5, interacts with collagen IV and nidogen-2 (the proteins nidogen-2 and NID-2/1 are essential basement membrane components). Weak binding has been demonstrated for collagen type XV.

Fibulins 1 and 2 show overlapping molecular interactions; both glycoproteins are detected in basement membranes, elastic fibers and other connective tissue structures. Fibulin 1, like fibulin 2, is a calcium-binding glycoprotein that is detectable in vertebrates in the blood and in the extracellular matrix. Fibulin-1 is detectable in basal membranes and elastic fibres. It interacts with numerous extracellular matrix proteins such as fibronectin, proteoglycans and tropoelastin (Liu G et al. 2016).

Fibulin 2 is expressed slightly later in embryogenesis than calcium-binding fibulin 1, and both fibulin types are expressed preferentially in the endocardium, in the valves of large vessels and in the perichondrium. They are also expressed in the vessels of the renal glomerula. Both fibulins bind to fibronectin, proteoglycans, tropoelastin and elastic fibres. In the blood, fibulin-1 binds fibrinogen.

Fibulin 3: The gene coding for fibulin 3 was initially identified as a gene that is highly upregulated in aged fibroblasts and in Werner syndrome. In this syndrome, a missense mutation (R345W) in the fibulin 3 gene has been identified. Furthermore, fibulin-3 is upregulated in various malignant tumors, such as malignant pleural mesothelioma.

Fibulin 4: Fibulin 4 is a protein of the extracellular matrix involved in elastogenesis. Mutations in the fibulin 5 gene are responsible for autosomal recessive cutis laxa (ARCL1A), a severe systemic disease with cutis laxa, emphysema and vascular disease (pulmonary artery stenosis). Fibulin-4 binds procollagen. The protein is essential for the integrity of the wall structure of large vessels (Papke CL et al. 2014).

Fibulin 5: fibulin 5 is a calcium-dependent protein of the extracellular matrix, which plays a major role in the organisation of tropoelastin monomers into small aggregates during elastogenesis. Fibulin-5 is jointly responsible for the correct structure of the elastic fibres. It is also involved in the adhesion of endothelial cells. The fibulin-5 gene has been identified as a gene that is upregulated during embryogenesis in large blood vessels. Furthermore, animal experiments have shown that fibulins 4 and 5 play an essential role in the development of elastic fibres. Both fibulins bind to tropoelastin in vitro. In some patients with cutis laxa, missense mutations in the fibulin 5 gene (FBLN5) have been detected. Finally, fibulin-5 "knock out" mice also showed a phenotype of clinical analogies to Cutis laxa (Loeys B et al. 2002). Also in mid-dermal elastolysis (L90.9), fibulins 4/5 are only expressed to a small extent intralesionally compared to the healthy skin environment.

In COPD patients(J44.99), an increased fibulin 5 concentration could be detected in the tissue. Likewise, increased fibulin-5 production was observed in idiopathic pulmonary fibrosis (J84.9).

Fibulin-5 is again detected in damage to large blood vessels and also in arteriosclerotic changes, although fibulin-5 is hardly detectable postnatally, in mature vessels. Fibulin-5 is produced by endothelial cells and smooth muscle cells of the vessel. Presumably, fibulin-5 thus contributes to the repair process of damaged vessels.

Fibulin 7: Fibulin 7 (Fbln7) is expressed in teeth by pre odontoblasts and odontoblasts. It is also expressed in blood vessels by endothelial cells.

Genes: FBLN1, FBLN2, FBLN3, FBLN4, FBLN5, FBLN7 and HMCN1

1. de Vega S et al (2014) A C-terminal fragment of fibulin-7 interacts with endothelial cells and inhibits their tube formation in culture. Arch Biochem Biophys 545:148-153.
2. Liu G et al (2016) Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases. JCI Insight 1(9). pii: e86380.
3. Loeys B et al (2002) Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum mole gene 11:2113-2118.
4. Papke CL et al (2014) Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies. Matrix Biol 37:142-149.