Minor collagens of the skin with not so minor functions (1)
The skin is an essential chemical and physical barrier between our bodies and the external environment, and it requires specific mechanical properties to perform this function. The extracellular matrix (ECM) of the skin contains proteins, such as collagens, elastin and fibronectin, as well as large sulphated proteoglycans. The collagens are the most abundant mammalian proteins and account for around 30% of the total protein mass in the human body, including more than 70% of the dry weight of the dermis. The collagen superfamily is an extensive and complex group that to date includes 28 genetically distinct members with 42 different α chains. There are 20 different types of collagen expressed within the skin. The fibrillar collagens I and III make up over 90% of collagens and account for the strength and stiffness of the tissue. The other minor collagens include those associated with the basement membrane (types IV, VII, XV and XVIII), dermal collagens (types V, VI, XII, XIV and XVI) and transmembrane collagens (types XIII and XVII).
Type IV collagen
Type IV collagen is a major component of the basement membrane in nearly every tissue, including the skin. Type IV collagen consists of three distinct heterotrimers: α1(IV)α1(IV)α2(IV) and α5(IV)α5(IV)α6(IV) forms expressed within the skin. A few rare cases of epidermal blistering in patients with auto-immune responses to the α5(IV) chain have been reported.
Type V collagen
Heterotrimer α1(V) α1(V)α2(V), it co-assembles with type I and type III collagens, forms heterotypic fibrils in tissues including skin. Type V collagen has been implicated in the pathogenesis of systemic sclerosis, where overexpression of abnormal type V collagen correlates with disease stage and activity. Type V collagen may also be involved in wound repair. In a mouse model of wound healing the pro-α3(V) chain co-localises with heparan sulphate via binding to an acidic portion of the pro-a3(V) chain as shown with immunoelectron microscopy and may be an essential component of the matrix required for the initiation of wound repair.
Type VI collagen
Type VI collagen is a microfibrillar collagen with a characteristic beaded filament structure and is expressed in many connective tissues. The main monomeric unit is a heterotrimer comprising α1(VI), α2(VI) and α3(VI). Type VI collagen serves as a repository for platelet-derived growth factor, keratinocyte growth factor, matrix metalloproteinases −1, −2, −3, −8 and −9, interleukin 2 and cytokine oncostatin M, thus mediating their activity and availability in the course of normal tissue turnover, fibrosis and wound healing. Type VI collagen can be both a positive and negative regulator of wound healing, and effective wound repair may require a specific level of expression.
Type VII collagen
Type VII collagen has a well established role in anchoring the epidermis to the dermis and the pathogenesis of the dystrophic epidermolysis bullosa (DEB) family of blistering skin diseases. Type VII collagen is a homotrimer of three collagen α1(VII) chains, and it contains a central triple helical domain flanked by two long, non-collagenous domains. The non-collagenous domains of the N-terminus (NC-1) present at either end of the fibril and bind directly to type IV collagen and laminin-332. Type VII collagen plays roles in basement membrane formation and re-epithelialisation during wound healing.
Type XII and XIV collagens
Type XII and XIV collagen are members of the FACIT (fibril-associated collagens with interrupted triple helices) family of collagens. Type XII collagen comprises homotrimers of α1(XII) and can be found in two distinct forms as a result of alternative splicing: a short and a long form. Type XIV collagen is also composed of homotrimers of α1(XIV).
Type XIII collagen
Type XIII collagen is a transmembrane collagen that is expressed in the epidermis, at both cell–cell contact sites and the dermal epidermal junction.
Type XV and XVIII collagens
Type XV and XVIII collagens are homotrimers that constitute the distinct family of multiplexins, and contain glycosaminoglycan chains, chondroitin sulphate chains in type XV and heparan sulphate chains in type XVIII, resulting in being also considered proteoglycans.
Type XVI collagen
In skin, Type XVI collagen is expressed in the papillary dermis and localises to the dermal–epidermal junction, close to collagen type VII, and is produced by both fibroblasts and keratinocytes. It is therefore thought to contribute to the structural integrity of the dermal–epidermal junction.
Type XVII collagen
Type XVII collagen is a homotrimeric, transmembrane collagen specifically expressed by basal keratinocytes and comprises a globular intracellular domain, a rod-like transmembrane domain, and a large extracellular domain (ECD) with 15 triple helical collagenous domains. The intracellular domain interacts with the β4 integrin and plectin and is therefore an important component of hemidesmosomes. Type XVII collagen is an auto-antigen for bullus pemphigoid and is often referred to as bullus pemphigoid 180 (BP180) or bullus pemphigoid auto-antigen 2 (BPAG2). The inflammatory auto-immune response generated by type XVII collagen results in non-scarring blister formation at the dermal epidermal junction.
Other collagens
Type XIX, XX, XXII, XXIII, XXIV, XXVII and XXVIII collagens have been reported to exist in the skin, but little is known about their exact function.
The minor collagens regulate a diverse, yet crucial, set of functions within the skin. Basement membrane collagens, such as types IV, VII, and XVII are essential for the structural integrity of the basement membrane zone and anchorage of the epidermis to the dermis. Interestingly, these membrane collagens are all associated with autoimmune responses, possibly pointing to a link of collagen tissue localisation with auto-immunity.