Using pre-clinical models of disease to define new targets to slow joint degeneration in osteoarthritis

The main overall aim of this project is to understand mechanisms of joint degeneration during osteoarthritis progression in order to define new targets for therapy.

Osteoarthritis (OA) is one of the top chronic disease in the world, with yet no available therapies to slow its development. It is characterised by a series of complex and interlinked structural tissue changes, including articular cartilage degradation and subchondral bone sclerosis, as well as ligament and meniscal pathology, and pain sensitivity. To understand the interaction between all these tissues during OA development, the use of preclinical models of disease are necessary.

In this project, the student will use mouse models of OA to define mechanisms by which OA progresses by assessing how the different tissues of the joints interact and contribute to overall joint pathology. Specifically, we will use a transgenic mouse in which the extracellular matrix protein fibrillin-1 (FBN1) is deleted in specific skeletal cells. We have shown that loss of FBN1 leads to severe OA in response to joint overloading and affects all tissues of the musculoskeletal system mimicking early ageing pathologies, also seen in Marfan syndrome patients.

The specific aims include to define the pathological consequences of depleting FBN1 in specific bone cells on the development of OA and their link to mechano-responses of cells. The student will use in vivo double transgenic mouse approaches with induction of OA using our proprietary non-invasive joint overloading model, along with state-of-the-art imaging (i.e. micro-CT) and histological protocols to measure structural changes to bone and joint tissues. In addition, multi-OMICS approaches on cells undergoing either in vivo or in vitro mechanical compression will be used to define specific cellular pathways and genomics activities modulated by loss of FBN1.

In this project, the student will be part of a multidisciplinary and diverse team, and will be supported in developing in vivo and in vitro skills, as well as assessing disease development from the whole individual down to the molecular level.