PHYSIOLOGICAL AND PATHOLOGICAL SECRETION OF CARTILAGE OLIGOMERIC MATRIX PROTEIN BY CELLS IN CULTURE

Abnormalities in cartilage oligomeric matrix protein (COMP), a pentame ric structural protein of the cartilage extracellular matrix, have bee n identified in pseudoachondroplasia and multiple epiphyseal dysplasia , two human autosomal dominant osteochondrodysplasias. However, the fu nction of the protein remains unknown. With the goal of establishing a model to study the mechanisms by which COMP mutations cause disease, we have analyzed synthesis and secretion of COMP in cultured chondrocy tes, tendon, and ligament cells. Pentameric protein detected inside of control cells suggested that pentamerization is an intracellular proc ess. Patient cells expressed mutant and normal RNA and secreted COMP a t levels similar to controls, suggesting that abnormal pentamers are l ikely to be found in the extracellular matrix. Inclusions within patie nt cartilage stained with anti-COMP antibodies, and cultured cells pre sented similar inclusions, indicating that presumably abnormal COMP pe ntamers are less efficiently secreted than normal molecules. We conclu de that the COMP disorders are likely to result from a combination of a decreased amount of COMP in the matrix and a dominant negative effec t due to the presence of abnormal pentamers in cartilage.