Research on cartilage is intensifying as efforts expand to discover disease-modifying drugs to treat or prevent osteoarthritis. Proteolytic damage to the collagen fabric of cartilage is a critical, and probably early, component of the pathogenesis of degenerative joint disease. Here we summarize recent findings on the unique heteromeric structure of cartilage collagen fibrils, including the key role of collagen IX, a covalently bonded fibril-adapter molecule. A highly specific pattern of cross-linking sites that involves all three component gene products strongly suggests that collagen IX has evolved to function as an inter-fibrillar network-bonding agent. This is supported from the genetic evidence that mutations in all three collagen IX genes can produce a phenotype in which cartilage matrix integrity and early-onset osteoarthritis are a feature. From the structure of the cartilage collagen heteropolymer we also predict a pivotal role for telopeptide (non-triplehelical) proteolytic cleavages in the remodelling and degradation of collagen fibrils.

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