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Project

Deciphering the role of Piezo1 in age-specific loss of mechanosensation in the skeleton in vivo.

Our skeleton is a highly dynamic organ reacting to the presence or absence of mechanical stimuli in a way that regular exercise has anabolic and advantageous effects on skeletal strength, whereas physical inactivity easily results in bone loss. Physical activity is therefore also a cornerstone in the prevention and treatment of several common disorders typifying our society nowadays, like osteoporosis. Characterized by severe bone loss and skeletal fractures, osteoporosis mostly affects people above the age of 50, i.e. the physically less active. However, young adults also have more sedentary lifestyles nowadays, with (temporary or otherwise) detrimental effects on their skeletal strength. Although these effects of mechanical stimuli on the skeleton are widely recognized, the mechanisms driving the translation of mechanical stimuli into the appropriate cellular and molecular response remain largely elusive. Very recently, the Piezo1 cation channel was discovered by us and others as an essential sensor of mechanical stimuli in several skeletal cell types, such as chondrocytes, osteoblasts and osteocytes. This was illustrated by a large variety of conditional knockout mouse models of Piezo1, that all demonstrated early-onset of osteoporosis with or without multiple fractures, and no longer reacted to mechanical stimuli. These first studies already highlighted a major role of Piezo1 in skeletal growth and disease, but the severity of their phenotypes also hampered the investigation of milder and more translational forms of defects in mechanosensation. The overall aim of the proposed project is therefore to now mimic and characterize induced loss of Piezo1-mediated mechanosensation in vivo at different ages. Therefore, we will investigate mice with inducible knockout of Piezo1 in bone or cartilage tissue in young and aged mice. The aim is to detect general or age-specific effects through in-depth phenotyping of the skeleton of these mice and to identify differences in circulating serum parameters contributing to these phenotypes. The skeleton of inducible knockout mice of Piezo1 in cartilage or bone tissue will be investigated in-depth by combining µCT analysis and histology, by which we will collect information on the structural and cellular properties of the skeleton. Overall, this project will inform us on the age-specific effects of loss of mechanosensation by Piezo1. Moreover, these results will undoubtedly also result in an improved understanding of the acute effects of, for example, a period of immobilization, low physical activity or a space flight on a young or older adult skeleton.
Date:1 Apr 2021 →  31 Jan 2022
Keywords:SIGNAL TRANSDUCTION, BONE METABOLISM, OSTEOPOROSIS, PHYSICAL PRACTICE
Disciplines:Genetics, Musculo-skeletal systems