title: Chondrocyte cell death and intracellular distribution of COMP and type IX collagen in the pseudoachondroplasia growth plate.
abstract: Cartilage oligomeric matrix protein (COMP) is a large extracellular matrix protein expressed in cartilage, ligament and tendon. Mutations in the COMP gene cause two dominantly inherited skeletal dysplasias, pseudoachondroplasia (PSACH) and Multiple Epiphyseal Dysplasia (MED/EDM1). We report on a novel point mutation D511Y in the seventh calcium-binding repeat of the COMP gene and the resulting iliac crest growth plate pathology. The PSACH iliac crest growth plate is comprised of a large region of resting chondrocytes above a narrow region composed of clusters of disorganized proliferative and hypertrophic chondrocytes. Chondrocytes in all zones show massive intracellular retention of COMP and the surrounding extracellular matrix is deficient in COMP. Moreover, the 511Y COMP mutation selectively affects type IX collagen as little is found in the growth plate matrix whereas type II collagen and aggrecan are abundant in the matrix. Chondrocyte remnants are observed in the chondrocyte clusters and dead cells are found throughout the growth plate. Apoptosis studies demonstrate an unusual pattern of TUNEL staining in the PSACH chondrocytes compared to the control growth plate. These in vivo findings support our previous observation that retention of COMP leads to chondrocyte death. These results also add to the increasing evidence that PSACH and EDM1 are rER storage diseases and that impaired linear growth and joint erosion are caused by the disruptive effect of massive amounts of COMP within the chondrocytes.
authors.affiliation: Division of Genetics and Genomic Biology, The Research Institute, University of Toronto, The Hospital for Sick Children, Toronto, Canada. jacqueline.t.hecht@uth.tmc.edu
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.forename: Outi
authors.initials: O
authors.lastname: Makitie
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hayes
authors.forename: Richard
authors.initials: R
authors.lastname: Haynes
authors.forename: Miki
authors.initials: M
authors.lastname: Susic
authors.forename: Dina
authors.initials: D
authors.lastname: Montufar-Solis
authors.forename: P Jackie
authors.initials: PJ
authors.lastname: Duke
authors.forename: William G
authors.initials: WG
authors.lastname: Cole
mesh_terms: D000130:Achondroplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053674:Aggrecans; D017209:Apoptosis; D064236:Cartilage Oligomeric Matrix Protein; D002648:Child; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D024043:Collagen Type II / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006132:Growth Plate / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007085:Ilium; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D037181:Lectins, C-Type; D064235:Matrilin Proteins; D017354:Point Mutation; D011509:Proteoglycans / Q000378:metabolism
chemical_list: D053674:Aggrecans; D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II; D024121:Collagen Type X; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D037181:Lectins, C-Type; D064235:Matrilin Proteins; D011509:Proteoglycans; C577553:TSP5 protein, human