Research Groups > Ray Boot-Handford
Recent key publications
Pirog, K. A., Jaka, O., Katakura, Y., Meadows, R. S., Kadler, K. E., Boot-Handford, R. P., and Briggs, M. D. (2010) A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Mol Genet 19, 52-64 PubMed link.
Rajpar, M. H., McDermott, B., Kung, L., Eardley, R., Knowles, L., Heeran, M., Thornton, D. J., Wilson, R., Bateman, J. F., Poulsom, R., Arvan, P., Kadler, K. E., Briggs, M. D., and Boot-Handford, R. P. (2009) Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet 5, e1000691 PubMed link.
Huxley-Jones, J., Robertson, D. L., and Boot-Handford, R. P. (2007) On the origins of the extracellular matrix in vertebrates, Matrix Biol 26, 2-11 PubMed link.
RAY BOOT-HANDFORD BSc, PhD
Cartilage, dwarfism and osteoarthritis.
Most of the bones of our skeletons including the long bones and digits develop and grow by way of a cartilage template in a process called endochondral ossification. Cartilage is an avascular tissue consisting of a single cell type, known as a chondrocyte, embedded within an abundant extracellular matrix (ECM) which is secreted by the chondrocytes. The cartilage template of the skeleton deposited during development is transformed to bone in a highly organised developmental sequence. Chondrocytes in the growth plate proliferate forming columns of flattened cells and then expand in volume or ‘hypertrophy’. At the base of the growth plate the hypertrophic chondrocytes calcify the cartilage and then die. Blood vessels in the underlying bone invade bringing osteoclast cells which degrade the calcified cartilage and osteoblasts which synthesis the new bone ECM. Hence, longitudinal bone growth is the result of the coordinated activities of proliferative and hypertrophic chondrocytes coupled to cartilage degradation and bone formation by way of vascular invasion. At puberty, the only cartilage remaining is that of the articular cartilage which lines the ends of long bones in joints. Mutations in the genes encoding the cartilage extracellular matrix proteins affect endochondral ossification and result in a range of diseases classed as chondrodysplasias the major feature which is usually dwarfism. Chondrodysplasias are often associated with early-onset osteoarthritis, a disease in which the articular cartilage degrades causing joint failure and significant pain. Interestingly, general osteoarthritis, whose prevalence increases with age, is associated with inappropriate activation of endochondral ossification in the articular chondrocytes.
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 all of these studies.
The scientific story
Work in my lab if focused on answering three questions relating to the structure and function of cartilage in development and disease. Firstly: What is the function of the novel cartilage collagen – type XXVII collagen? This collagen is a distant relative of the classical fibrillar collagens but appears to assemble into very thin fibrils rather than the much broader, cross-striated fibrils associated with the classical fibrillar collagens such as types I, II and III collagen. The expression pattern of collagen XXVII is unusual in that it is expressed by proliferative chondrocytes in the growth plate but it is also expressed by a variety of epithelial cell types in different tissues during development including lung, gonad and tooth. We have recently found that significant deletions in the collagenous domain of collagen XXVII cause a profound chondrodysplasia and a lung developmental defect in gene targeted mice (unpublished observations).
The second question we are focusing on is: 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.
Thirdly, we are using cell culture and in vivo models to test: Does alleviating ER stress by various pharmacological interventions reduce disease severity?