Collagens of Cartilage and the Intervertebral Disc

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DESCRIPTION (provided by applicant): This project is using advanced methods in protein analysis to study the complex polymeric assembly of collagens and associated proteins that frame the extracellular matrix of cartilages. Covalent cross-linking mechanisms that stabilize the network and non-covalent protein-protein interactions that drive the assembly are of particular interest. We aim to understand the mechanism of cross-linking of the type IX collagen molecule onto the type II collagen fibril, and the role in this of type XI collagen, another component of the heterotypic polymer. A molecular model of the collagen IX-collagen 11 interaction is being refined based on the placement of cross-linking residues. The properties of the short variant of the collagen IX molecule used in the intervertebral disc, compared with the long form of hyaline cartilage, are being determined. This includes studying how tryptophan (W)-containing allelic variants (polymorphisms) of two of the collagen IX chains (encoded by COL9A2 and COL9A3) can cause the reported increased risk of disc degeneration associated with these genotypes. Genotyped samples of human cartilage and disc tissue positive for the W-alleles are being analyzed to determine if the expressed collagen IX becomes post-translationally altered such that it could lead to accelerated disc degeneration and/or nerve root irritation. Collagen V and XI gene products and splicing variants expressed in the intervertebral disc are being characterized in terms of number of molecular species represented, for their covalent cross-linking partners in the matrix and N-propeptide domain binding interactions. The binding sites for matrilin-3, a protein that selectively binds to components of the collagen network, are being defined in the collagen subunits. Any additional covalently bonded molecular components of the collagen network will also be identified. The clinical significance of the work is in providing a basis in molecular structure for understanding processes through which articular cartilages and intervertebral discs may be at risk of being degraded during adult life. Since mechanical failure of the collagen framework of both tissues is a key, irreversible feature of age-related joint degeneration, new insights on molecular mechanisms may offer the basis of therapeutic advances.