The role of PIEZO ion channels in the musculoskeletal system

Abstract

PIEZO1 and PIEZO2 are mechanosensitive cation channels which are highly expressed in numerous tissues throughout the body and exhibit diverse, cell-specific functions in multiple organ systems. Within the musculoskeletal system, PIEZO1 functions to maintain muscle and bone mass, sense tendon stretch, and regulate senescence and apoptosis in response to mechanical stimuli within cartilage and the intervertebral disc. PIEZO2 is essential for transducing pain and touch sensations as well as proprioception in the nervous system, which can affect musculoskeletal health. PIEZO1 and PIEZO2 have been shown to act both independently as well as synergistically in different cell types. Conditions that alter PIEZO channel mechanosensitivity, such as inflammation or genetic mutations, can have drastic effects on these functions. For this reason, therapeutic approaches for PIEZO-related disease focus on altering PIEZO1 and/or PIEZO2 activity in a controlled manner, either through inhibition with small molecules, or through dietary control and supplementation to maintain a healthy cell membrane composition. While many opportunities to better understand PIEZO1 and PIEZO2 remain, the studies summarized in this review highlight how crucial PIEZO channels are to musculoskeletal health and point to promising possible avenues for their modulation as a therapeutic target.

Microglial Piezo1 mechanosensitive channel as a therapeutic target in Alzheimer’s disease

“…Ruthenium red and gadolinium are both nonspecific inhibitors of numerous cation channels and they inhibit Piezo1 by blocking calcium transport ( Southam et al, 2017 ; Harraz et al, 2022 ). Ruthenium red blocks the open conformation on the extracellular side in a voltage-dependent manner while gadolinium binds to phospholipids, thereby compacting the region of the cell membrane surrounding the channel and preventing it from opening ( Mulhall et al, 2023 ; Savadipour et al, 2023 ). The standard concentrations of both ruthenium red and gadolinium are 10 μM ( Vasileva et al, 2021 ; Yaganoglu et al, 2023 ).…”

Biomechanics of Chondrocytes and Chondrons in Healthy Conditions and Osteoarthritis: A Review of the Mechanical Characterisations at the Microscale

“…Regarding mechanically gated ion channels, Piezo-type mechanosensitive ion channel component 1 (Piezo 1), Piezo-type mechanosensitive ion channel component 2 (Piezo 2) and the transient receptor potential vanilloid 4 (TRPV4) are of particular interest in regulating calcium influx in chondrocytes [17]. These channels are mechanical sensors present in different cell types and they seem to be involved in different diseases [18][19][20].…”

Regulation of Bone by Mechanical Loading, Sex Hormones, and Nerves: Integration of Such Regulatory Complexity and Implications for Bone Loss during Space Flight and Post-Menopausal Osteoporosis

“…However, if the adaptation to a changing stress environment does not proceed at a rate that can be handled, allowing for time to alter cellular activities, the tissue can fatigue, and integrity compromised. While much research activity has focused on osteoblasts (OB) and osteoclasts (OC) in the regulation of bone, it is clear that the actual mechanical sensing cells may be the osteocytes [39] playing a regulatory role in bone [40,41], potentially using cellular products in the cells from the piezo family of genes as sensors (discussed in [42][43][44]). Other cellular components, such as the parathyroid hormone receptor type 1 may also be involved in mechanosensing by bone cells [45][46][47].…”