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Human Molecular Genetics Advance Access published online on May 21, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm121
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation

Matthew P Leighton1, Seema Nundlall1, Tobias Starborg1, Roger S Meadows1, Farhana Suleman1, Lynette Knowles1, Raimund Wagener2, David J Thornton1, Karl E Kadler1, Raymond P Boot-Handford1 and Michael D Briggs1,*

1 Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK 2 Center for Biochemistry, University of Cologne, Germany

* Correspondence should be addressed to: Dr Mike Briggs Wellcome Trust Centre for Cell Matrix Research Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK, +44 161 275 5082(Tel), +44 161 275 5642(Fax), mike.briggs{at}manchester.ac.uk

Received April 1, 2007; Revised April 27, 2007; Accepted April 27, 2007

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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