Emerging roles of Piezo1 channels in bone: Cells and diseases

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To the Editor: Mechanotransduction is crucial for cellular and tissue adaptation to mechanical stimuli. Piezo1 channels, key mechanosensitive ion channels, confer sensitivity to these cues. Bone remodels in response to mechanical stimuli, maintaining homeostasis. Accumulated scientific evidence underscores the mechanosensitivity of both skeletal lineage cells and osteoclasts, marked by their robust expression of Piezo1 channels. Furthermore, insights garnered from bone-related studies have illuminated the indispensable function of Piezo1 in orchestrating bone development, repair processes, and other mechanobiology-driven activities. Roles of Piezo1 in mesenchymal stem cells (MSCs). A study in 2017 identified Piezo1 as a pivotal regulator of bone MSCs (BMSCs) under hydrostatic pressure, facilitating osteoblast differentiation via bone morphogenetic protein 2 upregulation while inhibiting adipogenesis. Conversely, Piezo1 inhibition attenuated osteoblast differentiation.[1] Subsequent investigations corroborated these findings, demonstrating that Piezo1 deficiency in BMSCs impairs osteoblast differentiation, exacerbates bone resorption, and precipitates spontaneous fractures in neonatal mice.[2] Beyond differentiation, Piezo1 also governs MSC migration. A study utilizing rat dental pulp-derived MSCs (DP-MSCs) as a model, explored Piezo1’s function in migration through manipulation of Ca2+ responses. This study revealed Piezo1’s stimulation of MSC migration via ATP release, which triggered P2 receptor-mediated purinergic signaling and downstream activation of proline-rich tyrosine kinase 2 (PYK2) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathways.[3] Roles of Piezo1 in osteoblasts. Data from the BioGPS database underscores the robust expression of Piezo1 in osteoblasts. Sun et al’s[4] seminal study, utilizing conditional Piezo1 knockout mice and tail-suspended models, illuminated the pivotal role of Piezo1 in osteoblasts. Their findings revealed that Piezo1 ablation disrupted osteogenesis, compromising bone formation, integrity, and strength through perturbations in Ca2+ signaling pathways. Notably, Piezo1 deficiency mitigated simulated microgravity-induced bone loss and attenuated mechanically activated currents, suggesting that reduced loading may suppress Piezo1 expression and hinder osteogenesis. In addition, reduced Piezo1 expression in osteoporosis (OP) patients underscores its clinical relevance to osteoblast dysfunction. This study constructed three models, elucidating Piezo1’s role in osteoblasts during bone formation and identifying a potential therapeutic target for OP and mechanical unloading-induced bone loss. A parallel investigation revealed that Piezo1 deficiency in osteoblasts accelerated bone loss and spontaneous fractures through enhanced bone resorption, with Piezo1-knockdown mice displaying resilience to bone mass and resorption reduction induced by tail suspension, highlighting Piezo1’s regulatory role in bone remodeling via osteoblast-osteoclast crosstalk. Further mechanisms implicated Piezo1 in osteoblasts as a regulator of Yes-associated protein (YAP)-dependent type II and IX collagen expression, influencing osteoblast differentiation.[5] Another study explored Piezo1’s involvement in fluid stress-induced signaling, demonstrating that fluid shear stress induced osteogenic Runx2 expression, which Piezo1 siRNA suppressed via the AKT/GSK-3/β-Catenin pathway.[6] Roles of Piezo1 in osteocytes. nels have emerged as a genetic Piezo1 deficiency in osteocytes was associated with reduced cortical thickness, cancellous bone volume, and an attenuated anabolic bone response in mice models. Notably, Yoda1 administration promoted bone mass accretion through Ca2+ channels, emphasizing Piezo1’s potential as a facilitator of bone anabolism and a viable therapeutic target.[7] Researchers analyzed Piezo1 expression in IDG-SW3 osteocytic cells, discovering that Piezo1 activation by Yoda1 significantly elevated intracellular Ca2+ levels while inhibiting sclerostin expression. Similarly, mechanical stretching exerted an analogous effect by reducing sclerostin expression, an outcome that was negated in the presence of GsMTx4 or Piezo1 knockout. Subsequent inquiries unveiled that mechanical stretching facilitated Akt phosphorylation, ultimately diminishing sclerostin expression in osteocytes via Piezo1.[8] In a parallel investigation, Piezo1’s mediation of fluid shear stress was illuminated, showcasing its ability to modulate the NOTCH3 pathway in MLO-Y4 osteocytic cells, leading to the upregulation of osteoprotegerin and downregulation of RANKL.[9] Furthermore, a study demonstrated that low-magnitude, high-frequency vibration activates osteocytes via Piezo1, inhibiting breast cancer extravasation to bone.[10] Although the complete signaling cascade remains to be fully elucidated, this research introduces an innovative approach for mitigating bone metastasis in breast cancer patients. Roles of Piezo1 in chondrocytes. Manipulations involving Piezo1 revealed intricate roles in chondrocyte biology, with Piezo1 knockdown fostering proliferation, whereas Piezo1 activation by Yoda1 hindered this process. Concurrently, GsMTx4 treatment mitigated chondrocyte mortality subsequent to mechanical injury.[11] Applying physical forces using high-speed clamps and elastomeric pillar arrays underscored Piezo1’s mediation of stretch-activated currents, though excessive loading diminished chondrocyte survival.[12] Piezo1 activation augmented Ca2+ concentrations and reactive oxygen species (ROS) levels, ultimately precipitating chondrocyte senescence.[13] Notably, the endogenous peptide urocortin 1 (Ucn1) inhibited Piezo1 channel activity through cAMP elevation, deactivating phospholipase A2 (PLA2) and mitigating chondrocyte apoptosis.[14] Prior research correlated Piezo1 expression with mechanical stretching duration, indicating its regulatory influence on chondrocyte proliferation.[15] Interestingly, chondrocyte-specific Piezo1 knockdown in mice led to premature OP onset, multiple fractures, abnormal osteoblast morphology, and impaired secondary spongiosa formation, initially elucidating Piezo1’s central role in endochondral ossification.[16] Roles of Piezo1 in osteoclasts. A study utilizing Piezo1 conditional-knockout mice elucidated the consequences of Piezo1 deficiency in osteoclasts, revealing facilitated bone resorption and bone loss phenomena, reminiscent of mechanical unloading states. Subsequent analyses demonstrated that the absence of Piezo1 hindered type II and IX collagen production via diminished YAP nuclear localization, which accelerated bone resorption processes.[5] Reinforcing these discoveries, a rat model of orthodontic tooth movement, leveraging Tartrate-resistant acid phosphatase (TRAP)-positive cells and RANKL/OPG ratios as osteoclastic activity markers, exhibited notably elevated TRAP-positive cells and RANKL/OPG expression. This observation underscores the pivotal role of Piezo1 channels in osteoclastogenesis.[17] Roles of Piezo1 in Osteoporosis (OP).Piezo1 channels have emerged as a genetic factor governing bone mineral density in humans, with diminished protein expression observed in OP patients.[4] Wu et al[18] explored the impact of piezoelectric micro-vibration stimulation (PMVS; 120 Hz) on OP, revealing its ameliorative effects on bone density, microstructure, and bone strength in ovariectomized mice. This intervention upregulated Piezo1 in osteoblasts while suppressing Dickkopf-related protein 1 (Dkk1), underscoring PMVS’s potential as a non-pharmacological strategy for postmenopausal OP, albeit its efficacy in hormone-independent OP awaits exploration. Hu et al[19] delved into Piezo1’s central role in spaceflight-induced bone loss, employing the hindlimb suspension model to simulate microgravity. They found that microgravity notably suppressed Piezo1 expression, and mechanistic investigations affirmed the Piezo1/β-catenin/ATF4 pathway’s essentiality in fostering BMSC proliferation and osteogenic differentiation. Roles of Piezo1 in Osteoarthritis (OA). Mechanically induced upregulation of Piezo1 in chondrocytes may exacerbate chondrocyte apoptosis, accelerating cartilage degeneration, a fundamental OA pathogenesis. Notably, the G protein-coupled estrogen receptor emerges as a pivotal regulator, suppressing Piezo1 activation via upregulation of YAP, Rho GTPase activating protein 29, and subsequent mediation of RhoA/LIMK/cofilin activation and actin polymerization, thereby safeguarding against chondrocyte apoptosis and OA advancement.[20] Lee et al[21] conducted an investigation into the interplay between interleukin-1 (IL-1)-mediated inflammatory signaling in OA and Piezo1 functionality, thereby suggesting Piezo1 as a promising therapeutic target for OA management. Their findings revealed that exposure to OA-relevant concentrations of proinflammatory IL-1α, over a 72-hour period, augmented Piezo1 expression, leading to elevated baseline Ca2+ levels and heightened chondrocyte sensitivity and vulnerability to mechanical insult. This study uniquely delved into how the OA microenvironment modulates Piezo1 function and its downstream signaling cascades, emphasizing the significance of this regulatory mechanism for future OA therapeutic strategies. Roles of Piezo1 in Osteosarcoma (OS).Piezo1 channels emerged as key players in OS progression. Utilizing an in vitro mechanical stretch model, investigators demonstrated that Piezo1 augments OS cell apoptosis elicited by mechanical stretching while concurrently suppressing proliferation. In vivo experiments utilizing Piezo1-specific short hairpin RNA (Piezo1-shRNA) to inhibit Piezo1 revealed an acceleration of tumor growth in nude mice.[22] This research illuminates Piezo1’s crucial role in OS pathogenesis, presenting a promising molecular target for therapeutic intervention in OS patients. Over the past decade, Piezo1’s multifaceted roles in human bone have garnered significant research attention. As a locomotive organ, bone senses and adapts to mechanical stimuli. Piezo1 channels, abundant in bone cells, are pivotal to maintaining bone homeostasis, and are also implicated in OP, OA, and OS. Despite progress, a comprehensive understanding of Piezo1-bone interactions remains elusive. Translating Piezo1 research into clinical therapies is challenging. Space travel’s microgravity environment poses risks, necessitating Piezo1-focused aerospace medicine research. Bone tissue engineering progresses rapidly, yet Piezo1’s post-implantation osteogenesis promotion and regulation pose challenges. Our knowledge of Piezo1’s enigmatic functions in bone health and future breakthroughs is still evolving. Funding This work was supported by grants from the Research Fund from the National Natural Science Foundation of China (Nos. 81971777, 12132012, 32100952). Conflicts of interest None.