Raymond Boot-Handford, BSc, PhD

ER stress as a pathogenic factor in cartilage

Work in my lab is focused on answering two questions relating to the structure and function of cartilage in development and disease. Firstly: What is the role of ER stress in the pathogenesis of diseases mediated by chondrocytes such as chondrodysplasias and osteoarthritis?  We have shown an association of ER stress with disease pathology using cell culture and in-house generated knock-in mouse models of chondrodysplasia caused by mutations in cartilage ECM genes such as collagen X, COMP and matrilin 3. Furthermore, by generating novel transgenic lines in which elevated ER stress (caused by the expression of a non-secreted, ER stress-inducing protein) is targeted to relevant chondrocytes in vivo by use of the collagen X or II promoter, we have demonstrated the capability of ER stress to induce chondrodysplasia. Our current efforts are focused on genetically dissecting out the roles of different ER stress pathways in disease pathogenesis using a series of conditional ER stress-related mouse lines crossed with our own chondrodysplasia lines. We are also characterising the consequences of elevated ER stress in the pathogenesis of osteoarthritis using a mechanically-induced disease model.
Secondly, we are using cell culture and in vivo models to test: Does alleviating ER stress by various pharmacological interventions reduce disease severity? These approaches may lead to novel therapeutic opportunities for treating a variety of chondrodysplasias and osteoarthritis.
 

Most of the bones of our body develop and grow by way of a cartilage template in a process called endochondral ossification. Cartilage has a single cell type, known as the chondrocyte, which secretes the abundant extracellular matrix in which these cells are embedded. The cartilage template of the skeleton deposited during development is transformed to bone in a highly organised developmental sequence that drives bone growth. Mutations in the genes encoding the cartilage ECM affect the way in which our long bones grow and result in a range of diseases classed as chondrodysplasias, the major feature of which is dwarfism. Chondrodysplasias are also often associated with early-onset osteoarthritis where the articular cartilage degrades causing joint failure and significant pain. Our studies are focused on understanding how cartilage ECM proteins function, defining the mechanisms by which mutations in cartilage proteins cause chondrodysplasia, and understanding the mechanisms by which osteoarthritis develops. Defining precisely the mechanisms by which these diseases develop has the potential to highlight new opportunities for treatment which is the long-term goal of these studies.

Ray lectures on the final year undergraduate course entitled Biochemical Basis of Disease.  He also actively participates in delivering Medicine Problem Based Learning and is a final year academic tutor for Medical Biochemistry.