title: Disruption of extracellular matrix structure may cause pseudoachondroplasia phenotypes in the absence of impaired cartilage oligomeric matrix protein secretion.
abstract: Pseudoachondroplasia and multiple epiphyseal dysplasia are two dominantly inherited chondrodysplasias associated with mutations in cartilage oligomeric matrix protein (COMP). The rarely available patient biopsies show lamellar inclusions in the endoplasmic reticulum. We studied the pathogenesis of these chondrodysplasias by expressing several disease-causing COMP mutations in bovine primary chondrocytes and found that COMP-associated chondrodysplasias are not exclusively storage diseases. Although COMP carrying the mutations D469Delta and D475N was retained within the endoplasmic reticulum, secretion of COMP H587R was only slightly retarded. All pseudoachondroplasia mutations impair cellular viability and cause a disruption of the extracellular matrix formed in alginate culture irrespective of the degree of cellular retention. The mutation D361Y associated with the clinically milder disease multiple epiphyseal dysplasia gave mild retention and limited matrix alterations, but the transfected cells showed normal viability. The effect of mutated COMP on matrix formation and cell-matrix interaction may be a major element in the pathogenesis of COMP-associated chondrodysplasias.
authors.affiliation: Center for Biochemistry and Center for Molecular Medicine, Medical Faculty, University of Cologne, Joseph-Stelzmann-Strasse 52, D-50931 Cologne.
authors.forename: Markus
authors.initials: M
authors.lastname: Schmitz
authors.forename: Alexander
authors.initials: A
authors.lastname: Becker
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmitz
authors.forename: Christian
authors.initials: C
authors.lastname: Weirich
authors.forename: Mats
authors.initials: M
authors.lastname: Paulsson
authors.forename: Frank
authors.initials: F
authors.lastname: Zaucke
authors.forename: Robert
authors.initials: R
authors.lastname: Dinser
mesh_terms: D000130:Achondroplasia / Q000235:genetics* / Q000473:pathology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry; D007202:Indicators and Reagents / Q000494:pharmacology; D009154:Mutation; D010641:Phenotype; D010957:Plasmids; D013778:Tetrazolium Salts / Q000494:pharmacology; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D016326:Extracellular Matrix Proteins; D007202:Indicators and Reagents; D013778:Tetrazolium Salts; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide