title: Expression of PSACH-associated mutant COMP in tendon fibroblasts leads to increased apoptotic cell death irrespective of the secretory characteristics of mutant COMP.
abstract: OBJECTIVE
  Pseudoachondroplasia (PSACH) is a dominantly inherited chondrodysplasia associated with mutations of cartilage oligomeric matrix protein (COMP), characterized clinically by disproportionate dwarfism and laxity of joints and ligaments. Studies in chondrocytes and cartilage biopsies suggest that the cartilage disease is caused by retention of mutant COMP in the endoplasmic reticulum of chondrocytes and by disruption of the collagen network of the extracellular matrix. The pathogenesis of the tendon disease remains unclear in the absence of a cell culture model, with available tendon biopsies leading to conflicting results with respect to the intracellular retention of mutant COMP.
  
  
  METHODS
  We established a cell culture model using adenoviral gene transfer in tendon fibroblast cultures. We compared the effect of expression of three PSACH-associated COMP mutants and the wildtype protein on COMP secretion, matrix composition and cellular viability.
  
  
  RESULTS
  Our results show that mutants D475N and D469Delta are retained within the endoplasmic reticulum of tendon cells similar to what is known from chondrocytes, whereas mutant H587R is secreted like wildtype COMP. In spite of this difference, the collagen I matrix formed in culture appears disturbed for all three mutants. All COMP-mutants induce apoptotic cell death irrespective of their differing secretion patterns.
  
  
  CONCLUSIONS
  Pathogenic pathways leading to tendon disease in humans appear to be heterogeneous between different COMP mutants.
authors.affiliation: Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Giessen, Kerckhoff Hospital, Benekestrasse 2-8, D-61231 Bad Nauheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weirich
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: Katja
authors.initials: K
authors.lastname: Kirsch
authors.forename: Matthias
authors.initials: M
authors.lastname: Heil
authors.forename: Elena
authors.initials: E
authors.lastname: Neumann
authors.forename: Robert
authors.initials: R
authors.lastname: Dinser
mesh_terms: D000130:Achondroplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D064236:Cartilage Oligomeric Matrix Protein; D002417:Cattle; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D064235:Matrilin Proteins; D009154:Mutation; D013710:Tendons / Q000378:metabolism*
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D003094:Collagen