COLLAGENS OF CARTILAGE AND THE INTERVERTEBRAL DISC

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This project is using advanced methods in protein chemistry to understand the polymeric architecture and interactions of the various molecular types of collagen that form the framework of cartilage and intervertebral disc tissue. The long-term objective is to define how the various kinds of collagenous protein are organized in the matrix, to what degree they are designed to self-assemble and interact with each other and with other matrix macromolecules in order to form the heteropolymeric fibrillar network. The need for molecular differences in the matrix architecture of different forms of cartilage and between regions within a single tissue, including junction domains with adjacent non-cartilaginous tissues, and the role of different collagen chemistries and modifying molecules are of particular interest. Two tissues, articular cartilage and intervertebral disc, will be studied in greatest detail using bovine and human sources. A focal topic is the manner of covalent intermolecular cross-linking and the scope of heterotypic polymerization in and between the collagen sub-families of molecules. Specific aims include defining precisely the molecular sites and chemistry of covalent interaction between types IX and II collagens, studying the incidence of cross- linking between types I and II collagens, defining the cross-linking mechanisms among the chain isotypes of the collagen V/XI sub-family of gene products, understanding the action of stromelysin and other extracellular proteases in degrading the cartilage collagen network and discovering the mechanism of cross-linking in type X collagen. The latest techniques in protein chemistry will be the primary approach, including HPLC peptide separations, gas-phase automated amino acid sequencing, specialized methods to detect and quantify the unique collagen cross- linking amino acids, and use of specific antibodies. The clinical significance of this work is in providing a molecular basis for understanding the processes whereby articular cartilage is degraded in osteoarthritic joints (osteoarthritis) and intervertebral discs break down with increasing adult age and contribute to common spinal disorders (low back pain). In both tissues a failure of the collagen framework is a central irreversible feature of the cartilage tissue degeneration. There is reason to believe that there may be common mechanisms of tissue destruction in joint cartilages and discs.