Type III Collagen, a Fibril Network Modifier in Articular Cartilage

Abstract

The collagen framework of hyaline cartilages, including articular cartilage, consists largely of type II collagen that matures from a cross-linked heteropolymeric fibril template of types II, IX, and XI collagens. In the articular cartilages of adult joints, type III collagen makes an appearance in varying amounts superimposed on the original collagen fibril network. In a study to understand better the structural role of type III collagen in cartilage, we find that type III collagen molecules with unprocessed N-propeptides are present in the extracellular matrix of adult human and bovine articular cartilages as covalently crosslinked polymers extensively cross-linked to type II collagen. Cross-link analyses revealed that telopeptides from both N and C termini of type III collagen were linked in the tissue to helical cross-linking sites in type II collagen. Reciprocally, telopeptides from type II collagen were recovered cross-linked to helical sites in type III collagen. Cross-linked peptides were also identified in which a trifunctional pyridinoline linked both an ␣1(II) and an ␣1(III) telopeptide to the ␣1(III) helix. This can only have arisen from a cross-link between three different collagen molecules, types II and III in register staggered by 4D from another type III molecule. Type III collagen is known to be prominent at sites of healing and repair in skin and other tissues. The present findings emphasize the role of type III collagen, which is synthesized in mature articular cartilage, as a covalent modifier that may add cohesion to a weakened, existing collagen type II fibril network as part of a chondrocyte healing response to matrix damage.Fibrillar collagens are the most abundant vertebrate proteins. They provide the extracellular framework and mechanical strength of most animal tissues. There are seven collagens in the fibrillar collagen family, types I, II, III, V, XI, XXIV, and XXVII, encoded by 11 distinct genes (for review see Ref. 1). Based on phylogenic analysis, fibrillar collagen genes can be subdivided into three distinct groups or clades (1-5). A-clade comprises ␣1(I), ␣1(II), ␣1(III), ␣2(I), and ␣2(V); B-clade is ␣1(V), ␣3(V), ␣1(XI), and ␣2(XI); and C-clade is ␣1(XXIV) and ␣1(XXVII). All fibrillar collagens are synthesized as procollagen molecules consisting of a long uninterrupted triple-helical domain (each ␣ chain contains about 1000 amino acid residues) with globular extensions at both N and C termini and a minor triple-helical domain in the removable N-propeptide (1, 6).Collagen types I, II, and III are the main fibril-forming molecules in vertebrates. Type I collagen is widely expressed and prominent in skin, tendon, bone and ligaments, and many other tissues but not in hyaline cartilages. The type I molecule is a heterotrimer of two ␣1(I) chains and one ␣2(I) chain (6). Type II collagen is restricted to cartilages, vitreous and intervertebral disc, and is a homotrimer of ␣1(II) chains (7-9). Type III collagen is also a homotrimer of ␣1(III) and appears to function as a copolymer wit...

Quantitative proteomics analysis of cartilage response to mechanical injury and cytokine treatment

“…Type III collagen molecules are present in the extracellular matrix of adult human and bovine articular cartilages extensively cross-linked to Type II collagen [36]. It has been hypothesized that Type III collagen may act as a covalent modifier that adds cohesion to a weakened, existing collagen type II fibril network as part of a chondrocyte healing response to matrix damage [36].…”

3‐D ultrastructure and collagen composition of healthy and overloaded human tendon: evidence of tenocyte and matrix buckling

“…The observation of increased type III collagen fits with the finding of higher type III collagen content in tendinopathy vs normal healthy tendon. It has been shown that type III pNcollagen is the main tissue form that can polymerize on the surface of type II collagen fibrils in articular cartilage in osteoarthritis (Wu et al, 2010) and on type I collagen in skin (Fleischmajer et al, 1990b). Thus it is likely that in tendinoapthy, type III collagen formation dominates and attaches to type I collagen fibrils in the structural adaptation to tendinopathy, most likely as type III pNcollagen.…”

“…Collagen was extracted by pepsin and run based on equal dry weight loads of starting tissue on 6% SDS-PAGE using an interrupted electrophoresis method that resolves type III collagen chains (Wu et al, 2010) adapted to the method of Laemmli (Laemmli et al, 1970). Individual protein bands after Coomassie Blue staining were digested in-gel by trypsin (Eyre et al, 2008, Kinter and Sherman, 2005).…”

Lysyl Oxidase Activity Is Required for Ordered Collagen Fibrillogenesis by Tendon Cells

“…Higher ratios of collagen types V/I are associated with thin fibrils as in cornea. Collagen types I, III, and V are cross-linked to each other in heterotypic fibrils (41)(42)(43)(44). Apart from collagen type V, decorin, fibromodulin, and tenascin-X regulate collagen fibril diameters (40,(45)(46)(47).…”