Expression of mutant cartilage oligomeric matrix protein in human chondrocytes induces the pseudoachondroplasia phenotype

Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society
Thomas M MerrittJacqueline T Hecht

Abstract

Over 70 mutations in the cartilage oligomeric matrix protein (COMP), a large extracellular pentameric glycoprotein synthesized by chondrocytes, have been identified as causing two skeletal dysplasias: multiple epiphyseal dysplasia (MED/EDM1), and a dwarfing condition, pseudoachondroplasia (PSACH). These mutations induce misfolding of intracellular COMP, resulting in retention of the protein in the rough endoplasmic reticulum (rER) of chondrocytes. This accumulation of COMP in the rER creates the phenotypic enlarged rER cisternae in the cells, which is believed to compromise chondrocyte function and eventually cause cell death. To study the molecular mechanisms involved with the disease, we sought to develop an in vitro model that recapitulates the PSACH phenotype. Normal human chondrocytes were transfected with wildtype (wt-) COMP or with mutant COMP (D469del; mt-) recombinant adenoviruses and grown in a nonattachment redifferentiating culture system that provides an environment allowing formation of a differentiated chondrocyte nodule. Visualization of normal cells expressing COMP suggested the hallmarks of the PSACH phenotype. Mutant COMP expressed in normal cells was retained in enlarged rER cisternae, which also retained IX...Continue Reading

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Citations

Aug 7, 2008·The Journal of Biological Chemistry·C Britt CarlsonDeane F Mosher
Sep 19, 2009·The American Journal of Pathology·Karen L PoseyJacqueline T Hecht
May 28, 2008·Injury·Andre F SteinertRocky S Tuan
Feb 20, 2007·Matrix Biology : Journal of the International Society for Matrix Biology·Christian WeirichRobert Dinser
Feb 13, 2008·Equine Veterinary Journal·W BackT A E Stout
Apr 11, 2015·Human Molecular Genetics·Karen L PoseyJacqueline T Hecht
Dec 14, 2011·The American Journal of Pathology·Françoise CoustryJacqueline T Hecht
Apr 30, 2020·Molecular Genetics & Genomic Medicine·Alexander BurgerKaren L Posey
Dec 17, 2018·The American Journal of Pathology·Karen L PoseyJacqueline T Hecht

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