Skeletal diseases are a large and diverse group of rare monogenic phenotypes and there are more than 450 unique and well-characterised chondrodysplasia phenotypes that range in severity from relatively mild to severe and lethal forms. Studying these genetically tractable chondrodysplasia phenotypes provides insight into disease pathways that may be relevant to the more common and polygenic forms of OA.
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) present with varying degrees of joint pain and stiffness, short stature and early onset osteoarthritis that often requires joint replacement within the 2nd or 3rd decade of life. PSACH and the severe forms of MED result from mutations in cartilage oligomeric matrix protein (COMP), whilst the more moderate and mild forms of MED result from mutations in matrilin-3 and type IX collagen respectively. Genetic variations in the genes encoding all three proteins have also been associated with OA through both family and/or genetic association studies.
To determine PSACH-MED disease mechanisms in vivo and provide knowledge on potential disease pathways in OA we generated a series of knock-in mouse models of PSACH-MED. Mutant mice develop mild to moderate short stature and display a growth plate dysplasia that is characterized by varying degrees of disrupted chondrocyte alignment, reduced chondrocyte proliferation, increased and/or spatially dysregulated apoptosis. Expression of mutant COMP and matrilin-3 induced either canonical or novel ER stress pathways. To relate the expression of mutant gene products to OA pathology we performed sequential protein extractions on the cartilage from COMP and matrilin-3 mice. We identified quantitative changes in the extraction of structural and non-structural ECM proteins, including proteins with roles in cellular processes such as protein folding and trafficking. In particular, genotype-specific differences in the extraction of collagens XIV and XII and tenascins C and X were identified. In summary the mutations of matrilin-3 and COMP lead to changes in the interactions of other cartilage proteins and our proteomic analyses revealed both common and discrete disease signatures that provide novel insight into mechanisms of skeletal disease and cartilage degradation.
17 May 2014 - 20 May 2014