Deciphering the role of Piezo proteins in mechanotransduction of bone cells

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The bone matrix is continuously remodeled through the balanced activities of two distinct cell types, bone-forming osteoblasts and bone-resorbing osteoclasts. Bone remodeling is also influenced by terminally differentiated osteoblasts, i.e. osteocytes, which form a cellular network within the mineralized bone matrix and presumably act as sensors of mechanical loading. Although several candidate molecules have been suggested to be involved in the mechanotransduction ability of osteocytes, the physiological complexity of the osteocyte network has hindered the establishment of a definite pathway primarily controlling the mechanobiology of the skeleton. One potentially relevant family of mechanosensitive ion channels is comprised of two proteins, Piezo1 and Piezo2. Although the physiological relevance of the two broadly expressed Piezo channels is just beginning to be unraveled, their impact on mechanotransduction has already been confirmed in various non-skeletal cell types. In our preliminary work related to this project we observed i) that mice with an osteoblast-specific Piezo1 inactivation display a severe osteoporotic phenotype ii) and that Piezo1 expression in osteoblasts is induced by mechanical stress, both in vitro and in vivo. These data strongly suggest that Piezo1 plays a key role in bone mass regulation in response to mechanical stimulation.Our working program aims at specifically inactivating Piezo1 and/or Piezo2 in the three different bone remodeling cell types and to analyze the respective mouse models at a cellular and molecular level. To demonstrate the potential role of Piezo1 in bone cell mechanotransduction we will apply the ulna loading model to monitor the response of mice lacking Piezo1 in osteoblasts or osteocytes. Finally, we will pursue a series of cell culture experiments to understand the function of Piezo proteins in bone cell mechanotransduction at a molecular level. We thereby expect to obtain novel and physiologically relevant insights into the mechanobiology of the skeleton.