Abstract |
Disruption to endochondral ossification leads to delayed and irregular bone formation and can result in a heterogeneous group of genetic disorders known as the chondrodysplasias. One such disorder, multiple epiphyseal dysplasia (MED), is characterized by mild dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the disease mechanisms that underpin the pathophysiology of MED we generated a murine model of epiphyseal dysplasia by knocking-in a matn3 mutation. Mice that are homozygous for the mutation develop a progressive dysplasia and have short-limbed dwarfism that is consistent in severity with the relevant human phenotype. Mutant matrilin-3 is retained within the rough endoplasmic reticulum of chondrocytes and is associated with an unfolded protein response. Eventually, there is reduced proliferation and spatially dysregulated apoptosis of chondrocytes in the cartilage growth plate, which is likely to be the cause of disrupted linear bone growth and the resulting short-limbed dwarfism in the mutant mice.
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Authors | Matthew P Leighton, Seema Nundlall, Tobias Starborg, Roger S Meadows, Farhana Suleman, Lynette Knowles, Raimund Wagener, David J Thornton, Karl E Kadler, Raymond P Boot-Handford, Michael D Briggs |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 16
Issue 14
Pg. 1728-41
(Jul 15 2007)
ISSN: 0964-6906 [Print] England |
PMID | 17517694
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Extracellular Matrix Proteins
- Matn3 protein, mouse
- Matrilin Proteins
- Molecular Chaperones
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Topics |
- Animals
- Apoptosis
- Cartilage
(metabolism)
- Cell Proliferation
- Chondrocytes
(cytology, metabolism)
- Disease Models, Animal
- Endoplasmic Reticulum
(metabolism)
- Extracellular Matrix Proteins
(genetics, physiology)
- Matrilin Proteins
- Mice
- Mice, Transgenic
- Models, Genetic
- Molecular Chaperones
(metabolism)
- Mutation
- Osteochondrodysplasias
(metabolism)
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