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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents



ID: 354776.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Expression of PSACH-associated mutant COMP in tendon fibroblasts leads to increased apoptotic cell death irrespective of the secretory characteristics of mutant COMP
Authors:Weirich, C.; Keene, D. R.; Kirsch, K.; Heil, M.; Neumann, E.; Dinser, R.
Date of Publication (YYYY-MM-DD):2007-05
Journal Abbrev.:Matrix Biol
Volume:26
Issue / Number:4
Start Page:314
End Page:323
Audience:Not Specified
Abstract / Description: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. CONCLUSION: Pathogenic pathways leading to tendon disease in humans appear to be heterogeneous between different COMP mutants.
Free Keywords:Achondroplasia/*genetics/metabolism/*pathology; Animals; *Apoptosis; Cattle; Cell Proliferation; Chondrocytes/metabolism; Collagen/metabolism; Disease Models, Animal; Extracellular Matrix/metabolism; Extracellular Matrix Proteins/*genetics/*physiology; Fibroblasts/*metabolism; Gene Transfer Techniques; Glycoproteins/*genetics/*physiology; Humans; *Mutation; Tendons/*metabolism
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=...
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