Using human genetics to reveal novel molecular pathways involved in mediating protective skeletal responses to exercise and mechanical loading
These research projects are in competition with 71 other studentship projects available across the GW4 BioMed MRC Doctoral Training Partnership. Up to 19 studentships will be awarded to the best applicants. Find out more information about the DTP including how to apply.
The skeleton’s adaptive response to mechanical loading is compromised in osteoporosis, causing bone fractures.
The project identifies molecular mechanisms underlying mechanical responses of the skeleton, implicated in osteoporosis. Cutting edge technologies involving human genetics and 3D models for studying bone mechanoresponses will be used.
Osteoporosis is a common age-related condition, where bone loss causes fractures, pain and frailty, with associated disability, mortality and healthcare costs. Bisphosphonates treat osteoporosis by suppressing bone resorption, but there are increasing concerns over side effects associated with their long term use. Theoretically, drugs that stimulate bone formation offer considerable advantages, however the only such agent currently available is teriparatide which has to be given by daily injection and is very expensive. A new bone-forming injection, romosozumab, is currently undergoing phase III trials. This is an antibody which blocks a protein called sclerostin, of which the latter contributes to the response of bone to mechanical loading and exercise. The present project is intended to identify further pathways involved in mechanical loading responses of bone, which could act as additional targets for bone-forming drugs.
The team in Bristol are carrying out cutting edge research in collaboration with international consortia, into the genetics of osteoporosis. Many new genes have recently been discovered in association with osteoporosis, using a variety of state-of-the-art methods. For example, their recent study based on UK biobank discovered over two hundred genes which had not previously been associated with bone mineral density (BMD). In addition, their UK-wide study of patients with extreme elevations in BMD has identified several new genes in which mutations produce substantial increases in BMD, leading to a similar clinical picture to sclerosteosis, the rare bone disorder leading to the discovery of sclerostin. Preliminary studies suggest that many of these new genes are active in bone, and have the potential to contribute to responses to mechanical loading, thereby representing exciting new drug targets.
In the present project, suitable genes will be identified from these human genetic studies, and their role in bone loading responses investigated in more detail using Cardiff's novel experimental bone model. In the model, osteocytes (the cells which sense bone loading) are cultured in 3D matrices deformed to mimic physiological loading of bone. We will use this system to identify which of the genes discovered in our genetic studies are stimulated in response to loading. Genes critical to this process will then be tested, by examining the effect of blocking each one in turn. Finally, the in vivo effect of knocking out identified candidate(s) will be examined in mice and zebrafish, in collaboration with Lee Meakin (School of Veterinary Medicine, University of Bristol) and Chrissy Hammond (School of Physiology and Pharmacology, University of Bristol).