Type VI Collagen: Its Biology and Value as a Biomarker of Hepatic Fibrosis

Review Article

Austin Biomark Diagn. 2014;1(2): 9.

Type VI Collagen: Its Biology and Value as a Biomarker of Hepatic Fibrosis

Ki M Mak*, Priya Sehgal and Cynthia K Harris

Department of Medical Education/Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, USA

*Corresponding author: Ki Mark Mak, Department of Medical Education/Center for Anatomy and FunctionalMorphology, Box 1007, One Gustave L. Levy Place, New York, NY, 10029, Icahn School of Medicine at Mount Sinai, New York, USA.

Received: October 27, 2014; Accepted: December 15, 2014; Published: December 16, 2014


Collagen VI forms a filamentous network in connective tissue, linking matrix macromolecules and cells. It is composed of three chains, α1(VI), α2(VI), and α3(VI), with a globular domain at each end. Additionally, three novel chains α4, α5, and α6 were identified. Intracellularly, collagen VI monomers dimerize and form tetramers, which are secreted and associate into microfilaments extracellularly. Collagen VI gene expression is regulated differently than I or III. Collagen VI interacts with fibronectin, mediates cell adhesion and promotes migration. Soluble collagen VI acts as a sensor for tissue damage, modulating mesenchymal cell proliferation and survival, matrix homeostasis, and wound healing. Three collagen VI-deficient mouse models have been generated, which have been used to investigate collagen VI-related myopathies, mammary carcinogenesis, and skeletal muscle satellite cell homeostasis. Collagen VI is upregulated in fibrosis of liver, skin, kidneys, lungs, heart, and adipose tissue. In the liver, collagen VI normally accounts for 0.1% of total collagen, but is increased 10-fold in cirrhosis. Elevated soluble collagen VI in circulation is considered an early biomarker of alcoholic liver fibrosis. Collagen VI immunostaining is enhanced in fibrotic foci, co-distributing with collagens I, III and V. Hepatic stellate cells (HSCs) are likely the source of perisinusoidal collagen VI. The α2(VI) chain sequesters hepatic matrix metalloproteinase (MMP)-1, -3, and -8 and blocks the enzymes' activation, preventing fibrolysis. CO6-MMP, a collagen VI fragment generated by MMP-2 and -9, is a specific biomarker of collagen VI degradation in experimental liver fibrogenesis. The collagen VI receptor on HSCs offers selective targets for anti-fibrotic agents.

Keywords: Filamentous Type VI collagen; Soluble collagen VI; Collagen VI assembly; Matrix metalloproeteinase; Biomarkers of liver fibrogenesis; Hepatic stellate cells


ECM: Extracellular Matrix; HSA: Human Serum Albumin; HSC: Hepatic Stellate Cell; MMP: Matrix Metalloproteinase; TGF-β: Transforming Growth Factor-β; BM: Bethlem Myopathy; MMTVPyMT: Mammary Tumor Virus-Polyoma Middle T antigen; ELISA: Enzyme-Linked Immunosorbent Assay


The microfilamentous type VI collagen is present in most connective tissue matrices where it forms a flexible filamentous network, linking matrix macromolecules and cells. This review presents an overview of the molecular structure, biosynthesis, assembly, degradation and biological functions of collagen VI, as well as mouse models of collagen VI deficiency. In particular, we review the role of soluble collagen VI as a stimulator of cell growth, promoter of cell survival, sensor molecule for tissue damage and modulator of connective tissue matrix homeostasis. The involvement of adipose tissue-derived soluble collagen VI in mouse mammary tumorigenesis is discussed. We summarize collagen VI's regulation of the self-renewal capacity of skeletal muscle satellite cells and muscle regeneration. This review highlights the up-regulation of type VI collagen in fibrotic disease of the liver, skin, lungs, kidneys, heart and adipose tissue, and specifically provides updated information on the action of collagen VI in liver fibrogenesis and its value as a biomarker of liver fibrosis.


Type VI collagen, designated by Furthmayr et al. [1], is classified as a non-fibrillar collagen, as opposed to the interstitial fibrillar collagens I, II and III. Along with type IV collagen of the basement membrane, collagen VI is grouped under the network-forming collagens [2]. It is widely distributed in most connective tissue matrices [3-6]. Chemically, collagen VI molecule is a heterotrimeric collagenous glycoprotein made of three genetically distinct α-chains, α1(VI), α2(VI) and α3(VI). These chains differ in molecular mass: 140 kDa for the α1 and α2 chains and 250 kDa for the α3 chain [7]. The monomer consists of two globular domains at the N- and Cterminals connected by a 105 nm long triple helix [2,4,8,9]. Uniquely, the triple helical domains are extensively linked by interchange disulfide bonds that most likely endow the collagen VI molecules with a higher thermal stability as well as protease resistance. The cDNAs of the three constituent chains of human collagen VI have been cloned and a large portion of the amino acids has been sequenced [8]. Of note, there are several Gly-Y-X triplet interruptions of the amino acid sequence that are thought to provide some flexibility to the collagen VI molecules. This is in contrasting to the non-interrupted Gly-Y-X repeats for the fibrillar collagens (as in collagen I) that endow the molecules with rigidity and the fibers with mechanical strength. The flexibility of collagen VI, however, is lower than that of collagen IV, which has similar short Gly-Y-X interruptions and contains larger ones comprising up to 20 residues. Another unique structural feature of collagen VI is that it contains the sequence Arg-Gly-Asp (RGD)- dependent cell attachment sites that probably function to interact with specific cell receptors belonging to the integrin family proteins. The genes for α1(VI) and α2(VI) chains are located on chromosomes 21, and the α3(VI) gene is located on chromosome 2 [7]. The major mRNA species encoding the chains of collagen VI have sizes of 4.2 kb (α1), 3.5 kb (α2), and 8.5 kb (α3).

More recently, three novel collagen VI genes (COL6A4, COL6A5, and COL6A6 located at a single locus on human chromosome 3q22.1) that encode the α4(VI), α5(VI), and α6(VI) chains have been identified [10,11]. These chains may substitute for the α3 chains, probably forming α1α2α4, α1α2α5, and α1α2α6 heterotrimers. Unlike the α1(V), α2(V), and α3(V) subunits, these collagen VI chains display a highly restricted tissue distribution pattern [12,13], raising the possibility of tissue specific roles for the chains in collagen VI assembly and function.

Synthesis, assembly and secretion

The biosynthesis of type VI collagen was studied in cultured human fibroblasts [14] and chick embryo fibroblasts [15] using [35S] methionine metabolic labeling of cells. Two labeled polypeptides of 140 and 260 kDa were identified in the cell layer lysates, matrices and media of the human fibroblast culture, while three polypeptides of 150kDa, 140 kDa and 260 kDa were identified in the chick embryo fibroblast culture media. These give rise, after pepsin digestion, to α1(VI), α2(VI) and α3(VI), respectively. Pulse-chase experiments in the embryo chick cells indicated that more than 60% of the labeled type VI collagen was present in the culture medium after a 4-hr chase duration. In both cell systems, the amounts of polypeptides deposited extracellularly were dependent on the presence of ascorbic acid and hydroxylation of prolines and lysines in the collagenous domains, as observed in fibrillar collagens [14,16]. But, unlike the fibrillar collagens, no proteolytic processing of the N- and C-terminal domains of the polypeptide chains occurred in collagen VI biosynthesis. Another study has shown that recombinant chicken α1(VI), α2(VI) and α3(VI) collagen chains can form monomers, dimers and tetramers in NIH/3T3 cell lines. These molecules were secreted into the culture matrix, forming fibrillar meshwork [17]. This model may offer a tool for analysis of type VI collagen assembly and deposition.

The collagen VI polypeptide structure from the human fibroblast culture has been examined by electron microscopy after rotary shadowing. The images revealed that the cell layer extracts contain monomers, dimers and tetramers of collagen VI and the culture matrices contain both tetramers and multimers, while only tetramers are present in the culture media [14]. The distribution of these molecules in various compartments of the culture likely reflects the various stages of collagen VI assembly in vivo as described below. Based on the data of rotary shadowed electron microscopy, physical and biochemical analyses, the sequence of events of collagen VI's intracellular assembly has been established [1,2,9,14,15,18]. In this model, as illustrated in Figure 1, two triple helical monomers of 105 nm in length from a dimer in an anti-parallel manner with a 75 nm overlap. Two dimers associate into a tetramer, with the chains stabilized by disulfide bonds [1,7,8]. Following secretion into the ECM, the tetramers assemble into filaments by end-to-end accretion, forming thin fibrils with prominent knobs at a periodicity of about 110 nm-so-called beaded-filaments [4,14,19]. The fibrils display a width of 6-10 nm; hence, collagen VI is also described as microfilamentous [20] or microfibrillar [9].