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 demonstrated that fibulins bind to tropoelastin. This binding was strong for fibulin-2 and -5, moderate for fibulin-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, also known as NID-2/1, are essential components of basement membranes). A weak binding affinity was demonstrated for collagen type XV.  

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

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

Fibulin 3: The gene encoding fibulin 3 was initially identified as a gene that is highly upregulated in aged fibroblasts and in Werner syndrome. A missense mutation (R345W) in the fibulin-3 gene (FBLN3) has been detected in this syndrome. Furthermore, fibulin-3 is upregulated in various malignant tumors, including malignant pleural mesothelioma.  

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

Fibulin 5: Fibulin 5 is a calcium-dependent extracellular matrix protein that plays a key role in elastogenesis by organizing tropoelastin monomers into small aggregates. Fibulin-5 is jointly responsible for the proper formation of elastic fibers. It is also involved in the adhesion of endothelial cells. The fibulin-5 gene has been identified as a gene that is upregulated in large blood vessels during embryogenesis. Furthermore, animal studies have demonstrated that fibulins 4 and 5 play an essential role in the development of elastic fibers. Both fibulins bind to tropoelastin in vitro. Missense mutations in the fibulin-5 gene (FBLN5) have been detected in some patients with cutis laxa. Finally, fibulin-5 “knockout” mice also exhibited a phenotype with clinical analogies to cutis laxa (Loeys B et al. 2002).  In mid-dermal elastolysis ( L90.9) as well, fibulins 4 and 5 are expressed only to a limited extent intralesionally compared to the surrounding healthy skin.

In COPD patients(J44.99), elevated levels of fibulin-5 were detected in the tissue. Similarly, increased fibulin-5 production was observed in idiopathic pulmonary fibrosis (J84.9).

Fibulin-5 is also detected in cases of damage to large blood vessels and in atherosclerotic changes, although it is scarcely detectable postnatally in mature vessels. Fibulin-5 is produced by endothelial cells and smooth muscle cells of the blood vessels. It is presumed that Fibulin-5 thus contributes to the repair process of damaged blood 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.