Grant: Project Grant

Physical forces are critical for successful function of many organs including bone; however, they also have a destructive potential. Many cell types, including bone cells, such as bone forming osteoblasts, sense and actively adapt to physical perturbations to prevent critical damage. ATP release is one of the earliest cellular responses to mechanical stimulation. ATP and related molecules act through receptors of P2 family, which includes seven P2X ligand gated ion channels and eight P2Y G-protein-coupled receptors. Even though abnormal ATP release and signaling have been implicated in mechanoadaptation, the coordination between this fast signaling and long-term changes in bone mass is poorly understood. In this project, we combine expertise in cellular and tissue mechanobiology of bone to: 1) To determine how mechanically-induced cell membrane injury, repair and ATP release change with ageing; 2) To resolve the roles of multiple P2 receptors in generating cellular responses that are adaptive to the force of mechanical forces; 3) To understand the contribution of mechanically-induced cell injury, repair and ATP release to age-related decrease in bone capacity for mechanoadaptation. Thus, we will determine the causative links between the i) exposure to mechanical force, ii) early cellular events, including micro-injury and repair, and ATP release and signaling, and iii) a mechanoadaptive response of bone tissue as an organ. Importantly, understanding molecular mechanisms of age-related decline in bone capacity for adaptation to mechanical stimuli will allow to personalize exercise regimes for people of different ages, in particular for elderly, in order to improve their effectiveness.