Dr Alvin Kwan - PhD
The regulation of chondrocyte maturation during endochondral ossification
Bones grow and repair mainly via a complex developmental process known as endochondral ossification in which ossification occurs within a specialised hyaline cartilaginous matrix. In the long bones, this hyaline cartilage is known as the epiphyseal growth plate. Within the growth plate, chondrocytes undergo a stringently controlled developmental sequence leading to terminal chondrocyte differentiation (cell hypertrophy) prior to the transition from cartilage to bone. Chondrocyte differentiation is therefore an important prerequisite of normal bone formation. Current research activities in my laboratory have focussed mainly on two potential regulators of cell differentiation in the growth plate.
Chick chronocyte spread on a type X collagen substrate showing focal contacts
- Type X collagen – an extracellular matrix molecule which forms a mat-like network around differentiating chondrocytes in the hypertrophic cartilage matrix. Its expression is reinitiated in mature articular cartilage in osteoarthritis and is thought to be the consequence of tissue repair and osteophyte formation. We have identified several receptors for type X collagen on the surface of hypertrophic chondrocytes, these include the integrin a 2b1 and the collagen receptors DDR1 and DDR2. We are particularly interested in studying the mechanisms of interactions, the biological effects and signalling events following receptor-type X binding.
- Small Acidic Protein (SAP) – a 172 amino acid bHLH-like nuclear protein which is downregulated during chondrocyte hypertrophy and by cyclopamine, an inhibitor of the Hedgehog signalling pathway. We hypothesise that SAP is a novel transcription factor that attenuates chondrocyte differentiation in the epiphyseal growth plate. We are interested in investigating the roles of SAP in endochondral ossification and the characterization of the Hedgehog-responsive element(s) of the SAP gene. We also study the regulation of SAP expression in other disease models such as atherosclerosis.
Drs. Farquharson & D. Jefferies, Roslin Institute ( Edinburgh), Midlothian, Scotland
Professor Vic Duance, Cardiff School of Biosciences, Cardiff University
Dr Birgit Leitinger, Division of Biomedical Sciences, Imperial College,London
Dr Sam Evans, Cardiff School of Engineering, Cardiff University
Dr Dipak Ramji, Cardiff School of Biosciences, Cardiff University
Dr Yoshiharu Mizui, Eisai Co. Ltd., Tsukuba Research Laboratories, Japan