Piezo1-mediated Mechanotransduction in the musculoskeletal system: Signaling networks and therapeutic perspectives

Abstract

Mechanical forces are integral to musculoskeletal homeostasis and pathology. Piezo1 is a mechanosensitive ion channel widely expressed in bone, cartilage, muscle, and tendon. It converts mechanical stimuli (tension, compression, shear) into Ca2+ influx and downstream signals, regulating proliferation, differentiation, metabolism, inflammation, and apoptosis. This review summarizes Piezo1's structure, gating mechanisms, tissue expression, and functions in the musculoskeletal system, focusing on cartilage degeneration, subchondral bone remodeling, skeletal remodeling, muscle maintenance, and tendon adaptation. Under physiological conditions, Piezo1 contributes to tissue homeostasis; however, under abnormal or sustained loads, excessive Piezo1 activation can disrupt Ca2+ balance, amplify inflammation, promote apoptosis, and contribute to pathological remodeling in osteoarthritis, osteoporosis, muscle injury, and tendon degeneration. Preclinical strategies, including chemical agonists/inhibitors, traditional Chinese medicine components, gene-based approaches, and stem-cell-related interventions, have been explored in cell and animal models. Piezo1 is an important mechanosensitive regulator linking mechanical cues to musculoskeletal biology, although its tissue-specific roles, interactions with other mechanosensitive channels, and clinical translational value require further study.