It is known that sympathetic nerve fibers are present in healthy and osteoarthritic synovium and that the sympathetic nervous system mediates numerous effects on adult skeletal system components. Furthermore, mechanical forces are critical for development and maintenance of normal cartilage structure. The existence of progenitor cells in healthy or osteoarthritic articular cartilage and their possible role in (osteoarthritis) OA manifestation has been confirmed. In recent chondrogenesis studies, we observed inhibition of chondrogenic extracellular matrix deposition and acceleration of chondrocyte hypertrophy after treatment with the sympathetic neurotransmitter norepinephrine (NE) at high concentrations under normoxic conditions. Additional experiments using adrenoceptor agonists and antagonists confirmed the involvement of b2-adrenoceptor. Our results suggest that NE may influence existing or migrating progenitor cells and play a role in the development and manifestation of OA. In this project, we will characterize NE-dependent b2-adrenoceptor-mediated signaling pathways responsible for effects on proliferation and chondrogenic differentiation of MSCs in detail with or without mechanical loading under normoxic and hypoxic conditions, because hypoxia reflects the physiological oxygen environment in cartilage tissue. Moreover, we will determine the effects of NE on OA manifestation and the involvement of b2-adrenoceptor in a murine experimental OA model. These experiments will allow new insight into the role of MSCs and sympathetic nerves in cartilage regeneration and OA development and might help to develop novel neuro-chondrogenic therapeutic options.