The acronym of my project is CHONDRION – Chondrocyte ion channel function and regulation in health and disease
Osteoarthritis (OA) is one of the ten most disabling musculoskeletal conditions in developed countries. The main risk factors for OA are age, genetic predisposition, obesity and prior joint injuries. However, the specific cause of the disease probably varies from individual to individual, and is usually unknown. The disease is characterised by the gradual degradation and loss of the shock-absorbing articular cartilage, changes in subchondral bone, and synovitis within the joint cavity. The primary target of OA is articular cartilage that covers the articulating surface of bones in synovial joints, allowing for almost frictionless transmission of forces towards the subchondral bone.
To date, no effective or curative treatment is available for OA. Current therapies are primarily targeted at reducing pain and inflammation. The unfavourable demographic changes suggest that both patient numbers as well as health care expenditures will double over the next 20 years in the EU, presenting a huge challenge to health services. Therefore, there is a pressing medical and socio-economic need for the development of novel cost-effective therapeutic strategies to preserve articular cartilage and its underlying bone, thus delaying the need for invasive and expensive surgical treatments.
In order to identify and develop state-of-the-art methods for effective treatment of OA cartilage there is an urgent need for a better understanding of normal and OA chondrocyte physiology. It is logical to assume that OA chondrocytes may be characterised by a transformed “membranome” and “surfaceome”– a different assembly of plasma membrane ion channels and transporters that regulate chondrocyte function and phenotype, and maintain communication with an altered extracellular matrix (ECM). As transition of healthy to OA chondrocytes includes changes in cell cycle and proliferation, as well as metabolic activity, a more detailed mapping of signalling pathways, cellular processes and membrane proteins involved is inevitable. In spite of the emerging role of plasma membrane ion channels in chondrocyte metabolism, proliferation and differentiation, many open questions remain concerning their involvement in signalling pathways and conversely, how various signalling pathways control the function of these channels, e.g. by phosphorylation/dephosphorylation and whether these regulatory mechanisms differ in healthy and inflammatory chondrocytes.
Therefore, the aim of my fellowship is to provide an advanced, multi-disciplinary training in chondrocyte biology, proteomics and electrophysiology in biomimetic models of OA through investigating the expression, function and regulation of plasma membrane ion channels and calcium signalling pathways of OA chondrocytes by using state of the art proteomic and electrophysiological techniques.
Correlating ion channel expression with altered function and dysregulated signalling pathways during the development of OA will provide a better understanding of pathophysiological mechanisms controlling disease progression and will contribute to the understanding of cartilage degeneration. After a preliminary training period, the first stage of the work will involve the exploration of healthy and inflammatory chondrocyte “channelome” using four complementary disciplines including transcriptomics, proteomics, bioinformatics and electrophysiology. The second stage will include the investigation of upstream and downstream calcium dependent and independent signalling pathways that differentially function in OA chondrocytes.
Sounds exciting, isn’t it? And ambitious… Here is a graphical summary of the hypothesis:
From time to time, I will share exciting new results and any progress made in the project.