The emerging role of Piezo1 in the musculoskeletal system and disease

Abstract

Piezo1, a mechanosensitive ion channel, has emerged as a key player in translating mechanical stimuli into biological signaling. Its involvement extends beyond physiological and pathological processes such as lymphatic vessel development, axon growth, vascular development, immunoregulation, and blood pressure regulation. The musculoskeletal system, responsible for structural support, movement, and homeostasis, has recently attracted attention regarding the significance of Piezo1. This review aims to provide a comprehensive summary of the current research on Piezo1 in the musculoskeletal system, highlighting its impact on bone formation, myogenesis, chondrogenesis, intervertebral disc homeostasis, tendon matrix cross-linking, and physical activity. Additionally, we explore the potential of targeting Piezo1 as a therapeutic approach for musculoskeletal disorders, including osteoporosis, muscle atrophy, intervertebral disc degeneration, and osteoarthritis.

Keywords: Piezo1; bone; cartilage; intervertebral disc; muscle.

Figure 1

Schematic diagram showing the crucial roles of Piezo1 in the musculoskeletal system. The left panel demonstrates that Piezo1 activation enhances bone formation and reduces bone resorption. However, Piezo1 activation accelerates chondrocyte damage and promotes nucleus pulposus (NP) and annulus fibrosus (AF) cell senescence and apoptosis. The right panel highlights the positive effects of Piezo1 activation on physical performance. Specifically, Piezo1 activation leads to increased blood flow redistribution and microvascular density in muscles. Furthermore, Piezo1 activation promotes myotube formation and increases tendon stiffness.

Figure 2

Piezo1 located in different cells regulates bone formation. (A) Mechanical stimulation by fluid shear stress (FSS), ECM rigidity, hydrostatic pressure (HP), and biomaterials (WP-TENG, D-PCL@A, and Yoda1 Bilayer membrane) activates Piezo1 channels in mesenchymal stem cells (MSCs), further activates downstream signaling pathway. (B) Activation of Piezo1 in osteoblasts (MSC-derived osteoblasts and MC3TC-E1) by FSS, LIPUS, Piezoelectric micro-vibration stimulation (PMVS), and increasing body weight, and the downstream signaling pathway. (C) FSS, mechanical stretch (MS), and Yoda1 activate Piezo1 in osteocytes to enhance bone formation. (D) Piezo1 mediates mechanical loading enhances M2 macrophage polarization and promotes proliferation, migration, and osteogenic differentiation of BMSCs via secreting TGF-β1. (E) Conditional knockout Piezo1 in endothelial cells (Piezo1^Cdh5Cre) impedes bone formation, while Piezo1 activation in intestinal epithelium inhibits bone formation mediated by 5-HT production. Created with BioRender.com.

Figure 3

Piezo1 mediated chondrocytes mechanotransduction and potential therapeutic targets for OA. (A) Inflammation cues increase the mechanosensitivity of chondrocytes mediated by Piezo1 to mechanical loading. (B) Mechanical overloading induces chondrocyte ferroptosis in OA via Piezo1 activation (C) Static magnetic field (SMF), and appropriate mechanical loading promotes BMSCs chondrogenic differentiation via Piezo1 activation. Urocortin-1 (Ucn1), G protein-coupled estrogen receptor (GPER), GsMTx4 (a peptide of Piezo1 inhibitor), and Artemisinin (ART) protect chondrocytes from damage to alleviate OA symptoms. Created with BioRender.com.

Figure 4

Piezo1 functions in skeletal muscle. (A) Piezo1 orchestrates muscle satellite cells (MuSCs) morphological states after muscle injury, which is essential for muscle regeneration and maintenance. Pharmacologically activate Piezo1 by Yoda1 prime MuSCs toward more “responsive” cells. (B) The inward translocation of phosphatidylserine is the precondition of Piezo1 activation. Piezo1 activation enhances myotube formation, MuSCs proliferation, and inhibits MuSCs senescence to promote muscle regeneration. In addition, Piezo1 downregulation results in muscle atrophy. Created with BioRender.com.

Figure 5

Piezo1 mediates apoptosis and senescence of NP and AF cells. (A) Piezo1 activation under excessive mechanical stimulation and stiff matrix triggers apoptosis and senescence of NP cells. (B) Excessive mechanical stimulation induces AF cell apoptosis via Piezo1 activation. Created with BioRender.com.