As a group of heterogeneous diseases the osteochondrodysplasias have a complex aetiology, but are likely to share similar bask mechanisms of disease initiation, progression and end-stage pathology. In this context the principle objective of the proposed work is to determine the molecular, cell and extracellular matrix pathology of three distinct chondrodysplasia phenotypes, which result from mutations in the C-terminal globular domains of two different structural proteins that are important for normal bone development. From this approach we can expect to identify common basic mechanisms and learn general principles about genotype-phenotype correlations in other chondrodysplasia phenotypes. These data will ultimately help in developing therapeutic strategies that might be targeted to a range of individual phenotypes. Specifically, we will generate knock-in mouse models of (i) pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) resulting from mutations in the C-terminal globular domain of cartilage oligomeric matrix protein (COMP), and (ii) metaphyseal chondrodysplasia type Schmid (MCDS) resulting from a mutation in the C-terminal globular domain of type X Collagen. We will use these targeted mouse models to determine in vivo the disease pathology by using immuno-histochemistry, transmission electron microscopy, in situ hybridisation and proteornics to study in-depth the affected tissues to understand the pathological sequence of events and secondary mechanisms of pathogenesis. Furthermore, we will use cells and tissues from these mice to develop in vitro approaches for studying the disease processes, thereby fully exploiting the targeted mouse models as we establish, test and compare in vivo/in vitro correlations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049547-03
Application #
6798824
Study Section
Special Emphasis Panel (ZAR1-TAS-B (O2))
Program Officer
Sharrock, William J
Project Start
2002-09-27
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$188,000
Indirect Cost
Name
University of Manchester
Department
Type
DUNS #
229894910
City
Manchester
State
Country
United Kingdom
Zip Code
Plumb, Darren A; Ferrara, Laila; Torbica, Tanja et al. (2011) Collagen XXVII organises the pericellular matrix in the growth plate. PLoS One 6:e29422
PirĂ³g, Katarzyna A; Briggs, Michael D (2010) Skeletal dysplasias associated with mild myopathy-a clinical and molecular review. J Biomed Biotechnol 2010:686457
Boot-Handford, Raymond P; Briggs, Michael D (2010) The unfolded protein response and its relevance to connective tissue diseases. Cell Tissue Res 339:197-211
Rajpar, M Helen; McDermott, Ben; Kung, Louise et al. (2009) Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet 5:e1000691
Pirog-Garcia, Katarzyna A; Meadows, Roger S; Knowles, Lynette et al. (2007) Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Hum Mol Genet 16:2072-88
Leighton, Matthew P; Nundlall, Seema; Starborg, Tobias et al. (2007) 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. Hum Mol Genet 16:1728-41