Cross-linking Adenosine Receptors - Estrogen receptors for OA treatment

The purpose of this project is to define how estrogen- and adenosine-receptors modulate each other in CD4+ T-cells during osteoarthritis (OA) development and how these pathways can be targeted for development of a new OA therapy. Alterations of the articular cartilage function and of the joint surrounding tissues lead to disease like OA.

OA is a chronic invalidating disease with a large social impact.

There is no cure and the treatments to manage symptoms, pharmacological and non-pharmacological therapies, are useful only for a limited time, after which joint replacement surgery is necessary.

Women have increased risk of developing OA compared to men and epidemiology studies suggest that hormonal alterations play an important role in OA development. It is now widely recognized that inflammation is an important disease mechanism in OA pathogenesis. In particular CD4+ T cells have been identified as triggers of cartilage degradation in OA.

CD4+ T cells express estrogen- and adenosine receptors, two important regulators of the immune system.

In a recently published article, I showed that female mice lacking one of the adenosine receptors, A2A (A2AR), develop spontaneous OA with significantly milder disease symptoms compared to males suggesting a protective effect of female sex hormones on OA development. Interestingly, it has been shown that estrogens can modulate the expression of adenosine receptors.

In this project, I am going to investigate the effect of pharmacological activation of estrogen receptors on the anti-inflammatory A2AR and the pro-inflammatory A2BR, and the involvement of their mutual interaction on CD4+ T cell proliferation, differentiation and migration ability.

Moreover, the effect of combined A2B adenosine receptor blocking and estrogen treatment will be tested as a strategy for reducing pain and disease progression in an OA mouse model.