A high throughput 3D bone culture system for pharmaceutical screening of new drugs for osteoporosis and osteoarthritis

This project builds on our expertise in 3D bone models to develop a high throughput screen where effects of physiological loading and genotype can be assessed. Osteocytes are embedded in 3D type I collagen matrix, overlaid with bone forming osteoblasts, which are loaded in a deformable plate using our loading rig (Vazquez et al. 2014). The model will apply physiological loading to human cells. The feasibility of incorporating genetic mutations and simple readouts will be tested. This will reveal new disease mechanisms associated with osteoporosis and osteoarthritis and provide a tool to screen new drugs for these diseases.

BACKGROUND: Healthy ageing is a major health and economical challenge. Osteoporosis (OP), osteoarthritis (OA) result in significant morbidity (fractures, pain, frailty, disability), mortality and healthcare costs. OP and OA are age-related, ‘silent’ conditions, in which symptoms are not evident until bone loss or joint damage has already occurred, when treatments cannot reverse the disease. Structural changes in bone drive OA and OP pathology. Mechanical forces exerted on bone during physical activity increase bone mass, and drive adaptation of bone structure. Signals resulting from mechanical loading are primarily generated from the osteocytes, within the mineralised bone matrix, which sense mechanical stimuli and translate them to the bone surfaces where they regulate bone formation by osteoblasts.

RESEARCH: We will identify interactions between genotype and mechanical loading in OP and OA to identify potential therapeutics for these diseases. We will (1) adapt our high throughput 3D co-cultures models of bone to incorporate human cells (2) mimic the loads which bone cells experience in humans in vivo (3) develop methodology to introduce genetic modifications into the cells, (4) develop assays to detect anabolic and catabolic responses. Responses to loading/genetic modifications will be assessed using established molecular and protein assays. Various transfection approaches will be tested.