I am interested in how the skeleton (cartilage/bone) is formed. The skeletal system has many important functions such as defining the shape of an organism, making locomotion of larger organisms possible, serving as a calcium reservoir, performing important endocrine functions and giving protection to vital organs (e.g. brain, lungs, and heart). In bone and cartilage elements, collagenous matrix is laid down in a tissue specific way giving these skeletal tissues their specific characteristics (e.g. cartilage is spongy, bone is mineralised) in the right place. Healthy bone is constantly remodelled (the complete human skeleton is slowly regenerated over approximately ten years) to repair microfractures caused by loading of bone. This depends on a fine balance of bone building cells (osteoblasts and osteocytes) and bone degrading cells (osteoclasts) to maintain the right amount of bone.

The most common bone disease is osteoporosis which is diagnosed by assessing bone mineral density in the clinic (by for example using a DXA scan). Low bone mineral density is the parameter to diagnose osteoporosis, which affects ~50% of women and ~33% of men above the age of 55. Low bone mineral density is caused by a reduction in calcified collagenous bone matrix caused by an altered balance of bone building cells and bone degrading cells. This results in brittle (porous) bones that fracture easily leading to serious, sometimes even life threatening, fractures in the hip, vertebrae, and long bones (ribs, femur etc.). The current clinical practice to treat osteoporosis is to mainly block osteo-catabolic (osteoclasts, bone degrading) pathways. These unfortunately do not fully recover bone mineral density and bone strength.  

To find bone building (osteo-anabolic) genetic factors for a bone metabolism disorder like osteoporosis we need to better understand the biology of bone formation and homeostasis (balance between osteoblast and osteoclast activity). My collaborative research is informed by large human genomic datasets (genome wide association studies, whole exome sequencing, pedigree studies) to identify important genetic factors in the population that alter bone mineral density. Large human genomic datasets of bone mineral density offer a great way to identify new bone mineral density genes however, these strategies produce 100s of potential genes. I am currently using a prioritisation pipeline to select the best candidates for studies in the lab. The aim is to find new osteoanabolic (stimulating osteoblasts and bone strength) genetic factors and study these in the lab to gather detailed biological information for these potential osteo-anabolic drug targets.

I am using the zebrafish as they allow relatively fast screening of these identified genes in a cost-effective way. As the genes and signalling pathways that are important in regulating the skeletal system are evolutionarily conserved, the zebrafish offers a way to model human skeletal disease genes. This means that these experiments will provide first line of evidence of the effects on the skeleton and help to inform further studies (i.e. in other model systems as well) to develop strategies to target the osteo-anabolic genetic factors and their pathways relevant for bone metabolism disorders.