Physiological and pathological secretion of cartilage oligomeric matrix protein by cells in culture.
Abnormalities in cartilage oligomeric matrix protein (COMP), a pentameric structural protein of the cartilage extracellular matrix, have been identified in pseudoachondroplasia and multiple epiphyseal dysplasia, two human autosomal dominant osteochondrodysplasias. However, the function 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 chondrocytes, tendon, and ligament cells. Pentameric protein detected inside of control cells suggested that pentamerization is an intracellular process. Patient cells expressed mutant and normal RNA and secreted COMP at levels similar to controls, suggesting that abnormal pentamers are likely to be found in the extracellular matrix. Inclusions within patient cartilage stained with anti-COMP antibodies, and cultured cells presented similar inclusions, indicating that presumably abnormal COMP pentamers are less efficiently secreted than normal molecules. We conclude that the COMP disorders are likely to result from a combination of a decreased amount of COMP in the matrix and a dominant negative effect due to the presence of abnormal pentamers in cartilage.
Délot
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Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns, Allen Cedars-Sinai Research Institute, and Departmentof Pediatrics, UCLA School of Medicine, Los Angeles, CA 90048, USA.
Brodie
S G
SG
King
L M
LM
Wilcox
W R
WR
Cohn
D H
DH
D001483:Base Sequence; D002356:Cartilage / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D064236:Cartilage Oligomeric Matrix Protein; D002478:Cells, Cultured; D017931:DNA Primers; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D064235:Matrilin Proteins; D008854:Microscopy, Electron
D064236:Cartilage Oligomeric Matrix Protein; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human