The Functional genomics team covers functional studies into:

A. Genes, pathways and networks regulating cartilage formation and maturation in skeletal growth;

Molecular control of chondrocyte differentiation, proliferation and terminal differentiation

The genes and factors that regulate the initial steps of chondrocyte differentiation, proliferation and entry into hypertrophy are relatively well characterized. In contrast, because all mouse mutants deficient in the Ihh, PTHrP, Bmp and Fgf pathways die perinatally, the mechanisms that control the terminal differentiation steps and the role of signals emanating from the cells themselves, especially from the postnatal period of rapid skeletal growth until the end of puberty, remain poorly understood. W e aim to dissect the molecular controls governing terminal differentiation, cell cycle regulation and cell death in hypertrophic chondrocytes in the fetal and post-natal period.

B. Skeletal disorders and degeneration

 The impact of protein misfolding on chondrocyte differentiation and the molecular pathogenesis of growth plate disorders

Many skeletal disorders arise because genetic defects perturb the growth or development of cartilage and bone (osteochondrodysplasia) or the formation of bone (dysostosis). These often result in abnormalities in the growth plate, ranging in severity from prenatal lethality to differing degrees of dwarfism. Many of the mutations produce deficiencies of key transcriptional regulators, ECM components or growth factors. Other mutations cause gain-of-function or dominant-negative effects owing to the synthesis of abnormal proteins. Once formed, the skeleton has to withstand a life-time of mechanical loads and physical insults. The influence of genetic factors on durability and propensity for degeneration of the skeleton has become increasingly evident through common degenerative disorders such as arthritis, osteoporosis and degenerative intervertebral disc disease (DDD). Genetic predisposition to these disorders results from the cumulative influence of many genetic factors.

In this part of the AoE programme, we focus on the impact of defects of protein folding and secretion on chondrocyte differentiation and the molecular pathogenesis of growth plate disorders. For example we aim to discover how ER stress impacts on cellular signalling pathways and differentiation and the molecular mechanism by which triggering ER stress results in phenotypic abnormalities in cartilage and bone.