Piezo1 and Piezo2 exhibit a high degree of structural homology (Jiang et al., 2021b). Both channels adopt a distinctive triskelion-like architecture consisting of a central ion-conducting pore domain, an apical extracellular dome, and tripartite curved blade subunits connected to helical beams gating three lateral portals (Ge et al., 2015; Wang et al., 2019; Yang et al., 2022) (Figure 1A).

Mechanical stimulation triggers conformational changes in Piezo channels. Specifically, the triskelion configuration distorts the bound lipid membranes into a nanobowl-like structure complex. This nanobowl-like complex flattens upon mechanical stimulation (Ge et al., 2015; Wang et al., 2019; Yang et al., 2022). The resulting flattening of the blades, coupled with the rotation of the cap and bending of the beams, facilitates cation signal transduction through the central pore and lateral portals (Ge et al., 2015; Wang et al., 2019; Yang et al., 2022). This finely tuned conformation underlies the high sensitivity of Piezo channels to mechanical forces, enabling them to modulate pathophysiological processes via cation-influx-triggered molecular signaling cascades (Figure 1B).

Piezo1 channels are gated by diverse mechanical perturbations such as poking, mechanical stretch, fluid shear stress (FSS), and hydrostatic pressure (HP), whereas Piezo2 is primarily responsive to poking and exhibits insensitivity to stretching (Sugimoto et al., 2017; Jiang et al., 2021b). Two primary paradigms govern the mechanoactivation of ion channels: the “force-from-lipids” model and the “force-from-filaments” model (Murthy et al., 2017). The former hypothesis emphasizes the mechanical energy transfer through lipid bilayer deformation under membrane interfacial tension (Arnadóttir and Chalfie, 2010). The latter hypothesis attributes stimulus transduction to molecular tethers coupling to extracellular matrix (ECM) proteins or cytoskeletal elements (Arnadóttir and Chalfie, 2010). Gating of Piezo is intimately linked to the deformations of the lipid (Cox et al., 2016; Cox et al., 2017), and cytoskeletal regulation of membrane tension may further modulate channel activity (Jin et al., 2020). Notably, the presence of the ECM enhances Piezo sensitivity, while its absence renders the channels less responsive to mechanical forces (Gaub and Müller, 2017).

Several synthetic agonists selective for Piezo1 have been identified, such as Yoda1 and Jedi1/2 (Syeda et al., 2015; Lacroix et al., 2018; Wang et al., 2018; Botello-Smith et al., 2019; Xiao, 2020). Yoda1, which is hydrophobic, activates Piezo1 possibly through a “molecular wedge mechanism,” inserting between two domains of the Piezo1 blade to promote blade extension and channel opening under subthreshold stimulation (Botello-Smith et al., 2019). However, mutations in the Piezo1 beam that abrogate Yoda1 activation suggest the involvement of additional, yet unidentified, mechanotransduction pathways (Botello-Smith et al., 2019). Moreover, Dooku1, a derivative of Yoda1, competitively blocks Yoda1-activated Piezo1-dependent Ca²⁺ signaling (Evans et al., 2018). In contrast, Piezo1 activation can be elicited by Jedi1/2, which are hydrophilic, through binding to the extracellular region of its blade structure and utilizing key mechanotransduction points in the beam (Wang et al., 2018; Xiao, 2020). Interestingly, Yoda1 and Jedi1/2 exert minimal effects on Piezo2. Nonspecific inhibitors, including GsMTx-4, FM1-43, polycationic ruthenium red (RR), streptomycin, and gadolinium, can block Piezo1/2-mediated ion signaling (Coste et al., 2010; Bae et al., 2011; Eijkelkamp et al., 2013; Xu et al., 2021). Among them, GsMTx-4 is the only known selective cation mechanical ion channel inhibitor by altering the surrounding membrane curvature (Bowman et al., 2007; Bae et al., 2011; Alcaino et al., 2017).

Bone marrow serves as the primary site for lifelong hematopoiesis and bone regeneration, processes that are governed by interactions between bone marrow resident cells including mesenchymal lineage cells, immune cells, hematopoietic stem/progenitor cells, endothelial cells, and neuronal cells (Baccin et al., 2020). The Piezo family, particularly Piezo1, is widely distributed across mesenchymal lineage cells, immunocytes, and endothelial cells within bone marrow niches, mediating physiological functions including bone regeneration and hematopoiesis.

Osteocytes encased in mineralized matrix serve as primary mechanosensory cells in bone tissues (Haelterman and Lim, 2019). Piezo1 vitally functions in osteocyte sensation of FSS, supported by in vivo evidence showing that modulation of Piezo1 alters the load-dependent bone formation (Li et al., 2019; Sun et al., 2019) (Figure 2E). Under mechanical loading, osteocytes balance bone remodeling by adjusting the receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin (OPG) ratio and sclerostin/dickkopf-related protein 1 (Sost/Dkk1)-mediated Wnt pathway (Nakashima et al., 2011; Robling and Bonewald, 2020; Karthik and Guntur, 2021). In vitro, MLO-Y4 osteocytes sense FSS through Piezo1, accompanied by upregulation of the bone formation factor OPG and downregulation of the bone resorption factor RANKL (Liu et al., 2022b). The mechanically induced Sost expression suppression in osteocytic cell line IDG-SW3 is abrogated by Piezo1 deficiency or inhibition and AKT inhibitors, suggesting that the Piezo1/AKT pathway may mediate this regulatory process (Sasaki et al., 2020). Collectively, Piezo1 regulates the transcription of critical osteogenic and osteoclastic markers of osteocytes and is fundamental to mechanosensitive osteocyte-mediated bone remodeling. Additionally, MLO-Y4 cells can detect stretching forces via Piezo1, which triggers calcium influx, transcriptional coactivator with PDZ-binding motif (TAZ) nuclear translocation, and ATP production—events that amplify BMSCs’ osteogenic capacity and may offer novel intervention strategies for mechanical bone remodeling (Ru et al., 2024).

High levels of Piezo1 expression are detected in periosteal stem cells (PSCs) as well as macrophages in the periosteum (Deng et al., 2022; Liu et al., 2022a) (Figure 2F). Studies have consistently demonstrated that Piezo1 is indispensable for PSC-mediated chondrogenesis, bone formation, and cartilaginous bone transformation during fracture repair (Liu et al., 2022a). This role may be attributed to Piezo1’s ability to enhance the migratory, osteogenic, and pro-angiogenic capacities of PSCs, primarily via the YAP/β-catenin pathway activation (Liu et al., 2022a). During the meniscal regeneration process, biomechanical stimulation triggers Piezo1-mediated Ca²⁺ influx, subsequently activating calcium/calmodulin-dependent protein kinase (CaMK) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), thus promoting the YAP/phosphorylated Smad2/3 (pSmad2/3)/SRY-related HMG-box 9 (SOX9) pathway (Yan et al., 2023). However, the mechanisms by which Piezo1 modulates cell migration and pro-angiogenic secretion of VEGF-A remain to be fully elucidated.

CD68⁺ macrophages are the most mechanosensitive type of macrophage in the periosteum (Deng et al., 2022) (Figure 2D). Mechanical loading activates Piezo1 in CD68+F4/80- macrophage subsets, driving their differentiation into the CD68+F4/80+ phenotypes (Deng et al., 2022). These differentiated macrophages secrete transforming growth factor beta 1 (TGF-β1) and thrombospondin-1 (Thbs1, a cytokine activating TGF-β1 by phosphorylating Smad2/3) to recruit osteoprogenitor cells (Deng et al., 2022). Additionally, mechanical strain-induced Ca²⁺ influx triggers p53 post-translational modification through coordinated acetylation/deacetylation dynamics (Cai et al., 2023). These epigenetic reprogrammings drive macrophage polarization toward an M2 reparative phenotype, enabling TGF-β1 secretion that stimulates BMSCs recruitment, clonal expansion, and osteogenic differentiation (Cai et al., 2023).

In mammals, Piezo2 serves as the primary mechanotransducer for proprioception (Woo et al., 2015). Loss of Piezo2 function in humans leads to prenatal proprioceptive impairment, triggering abnormalities in joint positioning and ultimately leading to bone disorders like hip dysplasia, scoliosis, and distal arthrogryposis (Coste et al., 2013; McMillin et al., 2014; Chesler et al., 2016; Delle Vedove et al., 2016; Haliloglu et al., 2017; Mahmud et al., 2017; Uehara et al., 2020). A study in mice further confirmed that selective Piezo2 deficiency in proprioceptive neurons—but not in chondro-osteoprogenitor lineages—resulted in skeletal malformations such as aberrant hip and spinal structure (Assaraf et al., 2020).

Dental tissues harbor various stem cell populations, exemplified by dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED), both demonstrating self-renewal and multipotency—attributes that make them promising for tissue engineering (Zhai et al., 2019) (Figure 3A). DPSCs are sensitive to mechanical stimulations, which promote their proliferation while reducing the viability and adhesive properties (Gaite et al., 2024). Yoda1-induced activation of Piezo1 enhances migration of human DPSCs (hDPSCs) via an ATP-dependent protein tyrosine kinase 2 (PYK2)/mitogen-activated protein kinase (MEK)/ERK signaling cascade (Mousawi et al., 2020), while mechanical or chemical activation of Piezo1 promotes osteogenic differentiation by modulating BMP2 expression (Sugimoto et al., 2017). Static pressure can increase the expression of Piezo2 in hDPSCs as well (Kang et al., 2024). In SHED, Piezo1 regulates the nuclear translocation of Runx2, which is essential for osteoblast and odontoblast differentiation (Miyazaki et al., 2019). Additionally, in dental follicle cells (DFCs), which are contributors to cementogenesis, periodontal ligament formation, and alveolar bone development (Zhou et al., 2019), Piezo1 activation via Wnt3a/β-catenin signaling promotes proliferation and osteoblastic lineage commitment (Xing et al., 2022) (Figure 3A).

Pulp pain is mediated by slow-conducted unmyelinated C-fibers and fast-conducted myelinated A-fibers (Bender, 2000). In pulpitis, inflammatory mediators lower the nociceptor thresholds, activating pain-associated ion channels (Yang et al., 2024). Piezo channels may contribute to the initial hyperemic response, potentially via Piezo2-mediated vascular mechanotransduction, given its detection in the blood vessel walls of human dental pulp (Gaite et al., 2024).

Piezo1 predominantly drives inflammatory progression, localizing to small myelinated Aδ fibers (60.2%), large myelinated Aβ fibers (24.3%), and unmyelinated C fibers (15.5%) (Bryniarska-Kubiak et al., 2024). Its expression increases progressively during irreversible pulpitis and correlates significantly with pro-inflammatory cytokines (interleukin-1beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α)) (Yang et al., 2024).

Piezo2 serves as the primary mechanonociception transducer, functioning as a low-threshold mechano-detector (Wan et al., 2024) enriched in Merkel cells and myelinated afferents (Ohyama et al., 2022). Critically, in peripheral pulp, both channels localize to unmyelinated axons ascending toward dentin, indicating their roles in mediating acute mechanical pain (Figure 3B) (Cho et al., 2022; Han et al., 2022). Piezo2 specifically facilitates glutamate release via vesicular transporters (Cho et al., 2022; Han et al., 2022). During irreversible pulpitis, Piezo2 downregulation occurs despite its strong association with pain mediators (neuropeptide Y (NPY), substance P, Tachykinin 1 (TAC1)) and overall pain intensity (Yang et al., 2024). Mechanistically, the cAMP signaling pathway potentiates Piezo2 mechanosensitivity in inflammation (Yang et al., 2024), consistent with its role in inflammatory mechanical hyperalgesia (Wan et al., 2024).

Collectively, although both Piezo1/2 are expressed on pulp nerve fibers and function as mechanosensitive channels directly involved in mediating pulp pain, they exhibit functional divergence: Piezo1 amplifies inflammatory responses while Piezo2 directly mediates nociception and may participate in vascular hyperemic responses. Their inverse expression dynamics highlight distinct pathophysiological roles.

In rodents, Piezo2 is predominantly expressed in mature odontoblasts (Khatibi Shahidi et al., 2015), while Piezo1 is primarily localized to the cell membrane and cytoplasm of human and murine odontoblasts (Huang et al., 2024). However, Gaite et al. (2024) proposed an alternative expression pattern in human teeth, demonstrating that Piezo1/2 are mainly present in pre-odontoblasts rather than mature odontoblasts and are absent in dentinal tubules. In contrast, murine odontoblasts exhibit widespread Piezo1/2 immunoreactivity, particularly at the basal pole (Gaite et al., 2024). These discrepancies are likely attributed to technical variations, highlighting the need for further investigation into Piezo channel localization in human odontoblasts.

Dentin sensitivity (DS) refers to pain arising from exposed dentin, not attributable to other dental diseases, and is best explained by hydrodynamic theory (Mantzourani and Sharma, 2013). According to this theoretical framework, external stimuli increase dentinal tubular fluid efflux, generating hydrodynamic shear stress on mechanosensory nerves in the tubules and then activating the Aδ nerve at the pulp-dentin junction, eventually leading to pain (Mantzourani and Sharma, 2013). Researchers demonstrate that Piezo1 and TRPV1/2/3/4 channels function as mechanosensors in this process, facilitating pannexin-1 (PANX1)-dependent ATP secretion, thereby establishing a communication pathway between odontoblasts and sensory neurons (Ohyama et al., 2022) (Figure 3C). Dental pain is triggered by P2X₃ receptor activation due to extracellular ATP release (Sato et al., 2018). Pharmacological blockade of the Piezo1/TRPA1-PANX1-P2X₃ axis in odontoblasts significantly reduces cold-induced pain responses in exposed dentin (Ohyama et al., 2022).

Additionally, Huang et al. (2024) revealed that Piezo1 promotes odontoblast mineralization in vitro via Ca²⁺/PI3K-AKT/semaphorin 3A (SEMA3A) by way of inducing hDPSCs to differentiate into odontoblasts, and they further confirmed its involvement in reactive dentin formation in vivo. Conversely, Matsunaga et al. (2021) identified that chemically activated Piezo1 inhibits the mineralization of odontoblasts, whereas knockdown of Piezo1 promotes the mineralization, and that Piezo1 is also vital for the suppression of dentinogenesis after cellular deformation within dentin tubules. These findings suggest that Piezo1 may exert context-dependent effects on odontoblast mineralization, warranting further investigation.

The cementum, which covers the root dentin and provides the anchor for the periodontal ligament (PDL) (Foster, 2017), is primarily composed of a mineralized matrix secreted by cementoblasts and collagen fibers derived from the PDL (Nuñez et al., 2019). The ability of cementoblasts to secrete mineralized matrix makes them pivotal in the formation of restorative cementum and the reconstruction of periodontal function (Nuñez et al., 2019). An in vitro study using the murine cementoblast model OCCM-30 confirmed the Piezo1 expression and found that the knockdown of Piezo1 exacerbated the decrease in the expression of cementogenic activity markers caused by static mechanical force (Zhang et al., 2017) (Figure 3D). Additionally, micro-CT imaging of Piezo1-knockout mice revealed marked reductions in cellular cementum, alveolar bone volume, and cementum ECM mass (Zhang et al., 2023), but this may result from diminished periodontal ligament stem cells (PDLSCs) differentiation into cementoblasts. In contrast, HP has been shown to increase Piezo1 expression in cementoblasts while suppressing cell migration and OPG expression, indicating that compressive forces impair cementoblast function by enhancing Piezo1 activity (Wang et al., 2023). Therefore, the precise role of Piezo1 in human cementogenesis and the underlying mechanisms involved remain to be further investigated.

OTM denotes the therapeutic application of controlled biomechanical forces to reposition misaligned dental units through coordinated periodontal remodeling (Jiang et al., 2021a). This biological process specifically involves structural adaptation of the periodontium components: alveolar bone, periodontal ligament (PDL), and gingiva (Jiang et al., 2021a). During OTM, the remodeling of tissues is triggered by the mechanical signal transduction of periodontal ligament cells (PDLCs) and osteocytes (Li et al., 2021). PDLCs exhibit dual expression of Piezo1 and Piezo2, with Piezo1 being more abundant (Horie et al., 2023). However, RR-mediated Piezo suppression has no effect on the proliferation of PDLCs (Gao et al., 2017). Activation of Piezo1 by Yoda1 promotes periodontal tissue regeneration through the stimulation of Lepr⁺ periodontal ligament stem cells (PDLSCs) (Zhang et al., 2023) and converts mechanical stimuli into intracellular calcium influx that modulates downstream signaling cascades such as Notch, ERK, nuclear factor kappa-Β (NF-κB), and so on (Jiang et al., 2024).

In a rat OTM model, Piezo1 activation on the tension side boosts osteogenic markers (Runx2, osterix (OSX), ALP, and collagen type I (COL1)) and elevates osteoclastic activity, both fundamental for alveolar bone remodeling (Jiang et al., 2021a) (Figure 3E). The non-canonical Wnt/Ca²⁺ pathway could be associated with this process, as indicated by correlations between Wnt5a/CAMKII expression and bone-related molecules on the tension side (Du and Yang, 2023). An in vitro study also showed that Piezo1 expression was upregulated in PDLCs after stretch loading, and this upregulation was closely related to stress-stimulated transcriptional activation of cyclooxygenase-2 (COX2) coupled with modulation of RANKL/OPG signaling axis in PDLCs (Shen et al., 2020). Furthermore, Piezo1 expression can be enhanced by mechanical tensile force in human PDLSCs (hPDLSCs), thus activating the Notch1 pathway and facilitating their osteogenic differentiation capacity (Lin et al., 2020).

Recent studies manifest that Piezo1 has an impact on pressure-triggered PDLC apoptosis (Jiang et al., 2024) and inflammatory gene expression (Schröder et al., 2023), while also promoting osteoclast differentiation (Zheng et al., 2024). Under mechanical pressure, Piezo1 activation in PDLCs elevates the expression of pro-inflammatory genes (TNF, IL-6, prostaglandin-endoperoxide synthase 2 (PTGS2)) (Schröder et al., 2023), upregulates pro-apoptotic proteins (Bax and caspase-3), and inhibits anti-apoptotic proteins, thereby promoting apoptosis via the p38/ERK1/2 pathway (Shen et al., 2023). Importantly, in the compression areas of OTM models, upregulated Piezo1 and β-catenin can be detected (Jiang et al., 2024), accompanied by increased RANKL/OPG ratios (Zheng et al., 2024). Inhibition of Piezo1 reduces the distance of tooth movement (Horie et al., 2023; Jiang et al., 2024). Interestingly, Piezo1 appears to mediate osteoclastogenesis in a context-dependent manner—upregulating RANKL under pressure while downregulating OPG in the absence of mechanical strain (Schröder et al., 2023). This may involve distinct intracellular signaling pathways, calling for further exploration. Additionally, Piezo1 on the PDLC membrane facilitates extracellular ATP release under compressive force, a mechanism that is critical for both bone remodeling and pain perception during orthodontic treatment (Horie et al., 2023).

Furthermore, immune cells including macrophages are recruited and play an integral regulatory role during OTM (Li et al., 2021). Early recruitment of M1 macrophages initiates osteoclastogenesis, whereas later recruitment of M2 macrophages suppresses osteoclastic activity and promotes bone deposition (Li et al., 2021). The Piezo1/AKT/cyclin D (Ccnd1) axis is essential for the proliferation and infiltration of macrophages in periodontal tissues during OTM (Xu et al., 2022) (Figure 3E). GsMTx4 also indirectly encourages the osteolytic differentiation of RAW264.7 by affecting the NF-κB pathway in periodontal ligament cells (Jin et al., 2015). Nevertheless, it remains enigmatic whether Piezo1 mediates macrophage polarization during OTM.