Cartilage oligomeric matrix protein interacts with type IX collagen, and disruptions to these interactions identify a pathogenetic mechanism in a bone dysplasia family

Cartilage oligomeric matrix protein (COMP) and type IX collagen are key str uctural components of the cartilage extracellular matrix and have important roles in tissue development and homeostasis. Mutations in the genes encodi ng these glycoproteins result in two related human bone dysplasias, pseudoa chondroplasia and multiple epiphyseal. dysplasia, which together comprise a "bone dysplasia family." It has been proposed that these diseases have a s imilar pathophysiology, which is highlighted by the fact that mutations in either the COMP or the type IX collagen genes produce multiple epiphyseal d ysplasia, suggesting that their gene products interact. To investigate the interactions between COMP and type IX collagen, we have used rotary shadowi ng electron microscopy and real time biomolecular (BIAcore) analysis. Analy sis of COMP-type IX collagen complexes demonstrated that COMP interacts wit h type IX collagen through the noncollagenous domains of type IX collagen a nd the C-terminal domain of COMP. Furthermore, peptide mapping identified a putative collagen-binding site that is associated with known human mutatio ns. These data provide evidence that disruptions to COMP-type IX collagen i nteractions define a pathogenetic mechanism in a bone dysplasia family.