title: A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia.
abstract: Pseudoachondroplasia (PSACH) results from mutations in cartilage oligomeric matrix protein (COMP) and the p.D469del mutation within the type III repeats of COMP accounts for approximately 30% of PSACH. To determine disease mechanisms of PSACH in vivo, we introduced the Comp D469del mutation into the mouse genome. Mutant animals were normal at birth but grew slower than their wild-type littermates and developed short-limb dwarfism. In the growth plates of mutant mice chondrocyte columns were reduced in number and poorly organized, while mutant COMP was retained within the endoplasmic reticulum (ER) of cells. Chondrocyte proliferation was reduced and apoptosis was both increased and spatially dysregulated. Previous studies on COMP mutations have shown mutant COMP is co-localized with chaperone proteins, and we have reported an unfolded protein response (UPR) in mouse models of PSACH-MED (multiple epiphyseal dysplasia) harboring mutations in Comp (T585M) and Matn3, Comp etc (V194D). However, we found no evidence of UPR in this mouse model of PSACH. In contrast, microarray analysis identified expression changes in groups of genes implicated in oxidative stress, cell cycle regulation, and apoptosis, which is consistent with the chondrocyte pathology. Overall, these data suggest that a novel form of chondrocyte stress triggered by the expression of mutant COMP is central to the pathogenesis of PSACH.
authors: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom.
authors: Farhana
authors: F
authors: Suleman
authors: Benedetta
authors: B
authors: Gualeni
authors: Hannah J
authors: HJ
authors: Gregson
authors: Matthew P
authors: MP
authors: Leighton
authors: Katarzyna A
authors: KA
authors: Piróg
authors: Sarah
authors: S
authors: Edwards
authors: Paul
authors: P
authors: Holden
authors: Raymond P
authors: RP
authors: Boot-Handford
authors: Michael D
authors: MD
authors: Briggs
mesh_terms: D000130:Achondroplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology; D064235:Matrilin Proteins; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010641:Phenotype
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins