Mechanosensory ion channels are proteins that are sensitive to mechanical forces. They are found in tissues throughout the body and play an important role in bone remodeling by sensing changes in mechanical stress and transmitting signals to bone-forming cells. Orthodontic tooth movement (OTM) is a prime example of mechanically induced bone remodeling. However, the cell-specific role of the ion channels Piezo1 and Piezo2 in OTM has not been investigated yet. Here we first identify the expression of PIEZO1/2 in the dentoalveolar hard tissues. Results showed that PIEZO1 was expressed in odontoblasts, osteoblasts, and osteocytes, while PIEZO2 was localized in odontoblasts and cementoblasts. We therefore used a Piezo1floxed/floxed mouse model in combination with Dmp1cre to inactivate Piezo1 in mature osteoblasts/cementoblasts, osteocytes/cementocytes, and odontoblasts. Inactivation of Piezo1 in these cells did not affect the overall morphology of the skull but caused significant bone loss in the craniofacial skeleton. Histological analysis revealed a significantly increased number of osteoclasts in Piezo1floxed/floxed;Dmp1cre mice, while osteoblasts were not affected. Despite this increased number of osteoclasts, orthodontic tooth movement was not altered in these mice. Our results suggest that despite Piezo1 being crucial for osteoclast function, it may be dispensable for mechanical sensing of bone remodeling.

Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Orthodontics University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Orthodontics University of Leipzig Medical Center Saxony Germany

Division of Plastic and Reconstructive Surgery Department of Surgery Stanford School of Medicine Stanford University Palo Alto CA USA

Institute of Osteology and Biomechanics University Medical Center Hamburg Eppendorf Hamburg Germany

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Robling AG, Turner CH. Mechanical signaling for bone modeling and remodeling. Crit. Rev. Eukaryot. Gene Expr. 2009;19(4):319–338. doi: 10.1615/CritRevEukarGeneExpr.v19.i4.50. PubMed DOI PMC

Vico L, Hargens A. Skeletal changes during and after spaceflight. Nat. Rev. Rheumatol. 2018;14(4):229–245. doi: 10.1038/nrrheum.2018.37. PubMed DOI

Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 2003;4(8):638–649. doi: 10.1038/nrg1122. PubMed DOI

Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature. 2003;423(6937):349–355. doi: 10.1038/nature01660. PubMed DOI

Kogianni G, Noble BS. The biology of osteocytes. Curr. Osteoporos. Rep. 2007;5(2):81–86. doi: 10.1007/s11914-007-0007-z. PubMed DOI

Niedźwiedzki T, Filipowska J. Bone remodeling in the context of cellular and systemic regulation: The role of osteocytes and the nervous system. J. Mol. Endocrinol. 2015;55(2):R23–36. doi: 10.1530/JME-15-0067. PubMed DOI

Dallas SL, Prideaux M, Bonewald LF. The Osteocyte: An endocrine cell … and more. Endocr. Rev. 2013;34(5):658–690. doi: 10.1210/er.2012-1026. PubMed DOI PMC

Murshid SA. The role of osteocytes during experimental orthodontic tooth movement: A review. Arch. Oral Biol. 2017;73:25–33. doi: 10.1016/j.archoralbio.2016.09.001. PubMed DOI

Shoji-Matsunaga A, Ono T, Hayashi M, Takayanagi H, Moriyama K, Nakashima T. Osteocyte regulation of orthodontic force-mediated tooth movement via RANKL expression. Sci. Rep. 2017;7(1):8753. doi: 10.1038/s41598-017-09326-7. PubMed DOI PMC

Moin S, Kalajzic Z, Utreja A, Nihara J, Wadhwa S, Uribe F, et al. Osteocyte death during orthodontic tooth movement in mice. Angle Orthod. 2014;84(6):1086–1092. doi: 10.2319/110713-813.1. PubMed DOI PMC

Matsumoto T, Iimura T, Ogura K, Moriyama K, Yamaguchi A. The role of osteocytes in bone resorption during orthodontic tooth movement. J. Dent. Res. 2013;92(4):340–345. doi: 10.1177/0022034513476037. PubMed DOI

Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010;330(6000):55–60. doi: 10.1126/science.1193270. PubMed DOI PMC

Li X, Han L, Nookaew I, Mannen E, Silva MJ, Almeida M, et al. Stimulation of Piezo1 by mechanical signals promotes bone anabolism. Elife. 2019;8:49631. doi: 10.7554/eLife.49631. PubMed DOI PMC

Sun W, Chi S, Li Y, Ling S, Tan Y, Xu Y, et al. The mechanosensitive Piezo1 channel is required for bone formation. Elife. 2019;8:47454. doi: 10.7554/eLife.47454. PubMed DOI PMC

Zhou T, Gao B, Fan Y, Liu Y, Feng S, Cong Q, et al. Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-ß-catenin. Elife. 2020;9:52779. doi: 10.7554/eLife.52779. PubMed DOI PMC

Wang L, You X, Lotinun S, Zhang L, Wu N, Zou W. Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat. Commun. 2020;11(1):282. doi: 10.1038/s41467-019-14146-6. PubMed DOI PMC

Hendrickx G, Fischer V, Liedert A, Kroge S, Haffner-Luntzer M, Brylka L, et al. Piezo1 inactivation in chondrocytes impairs trabecular bone formation. J. Bone Miner. Res. 2021;36(2):369–384. doi: 10.1002/jbmr.4198. PubMed DOI

Qin L, He T, Chen S, Yang D, Yi W, Cao H, et al. Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues. Bone Res. 2021;9(1):44. doi: 10.1038/s41413-021-00168-8. PubMed DOI PMC

Lin Y, Ren J, McGrath C. Mechanosensitive Piezo1 and Piezo2 ion channels in craniofacial development and dentistry: Recent advances and prospects. Front Physiol. 2022;13:103974. doi: 10.3389/fphys.2022.1039714. PubMed DOI PMC

Jiang Y, Guan Y, Lan Y, Chen S, Li T, Zou S, et al. Mechanosensitive Piezo1 in periodontal ligament cells promotes alveolar bone remodeling during orthodontic tooth movement. Front. Physiol. 2021;12:767136. doi: 10.3389/fphys.2021.767136. PubMed DOI PMC

Wen H, Gwathmey JK, Xie LH. Role of transient receptor potential canonical channels in heart physiology and pathophysiology. Front. Cardiovasc. Med. 2020;7:0024. doi: 10.3389/fcvm.2020.00024. PubMed DOI PMC

Logan DW. Hot to touch: The story of the 2021 Nobel Prize in physiology or medicine. Dis. Model Mech. 2021;14(10):049352. doi: 10.1242/dmm.049352. PubMed DOI PMC

Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature. 2014;516(7529):121–125. doi: 10.1038/nature13980. PubMed DOI PMC

Murthy SE, et al. The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci. Transl. Med. 2018;10(462):9897. doi: 10.1126/scitranslmed.aat9897. PubMed DOI PMC

Feng J, Luo J, Yang P, Du J, Kim BS, Hu H. Piezo2 channel–Merkel cell signaling modulates the conversion of touch to itch. Science. 2018;360(6388):530–533. doi: 10.1126/science.aar5703. PubMed DOI PMC

Sugisawa E, Takayama Y, Takemura N, Kondo T, Hatakeyama S, Kumagai Y, et al. RNA sensing by gut Piezo1 is essential for systemic serotonin synthesis. Cell. 2020;182(3):609–624.e21. doi: 10.1016/j.cell.2020.06.022. PubMed DOI

Assaraf E, Blecher R, Heinemann-Yerushalmi L, Krief S, Carmel Vinestock R, Biton IE, et al. Piezo2 expressed in proprioceptive neurons is essential for skeletal integrity. Nat. Commun. 2020;11(1):3168. doi: 10.1038/s41467-020-16971-6. PubMed DOI PMC

Luther J, Yorgan TA, Rolvien T, Ulsamer L, Koehne T, Liao N, et al. Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. Sci. Transl. Med. 2018;10(466):7137. doi: 10.1126/scitranslmed.aau7137. PubMed DOI

Uda Y, Azab E, Sun N, Shi C, Pajevic PD. Osteocyte mechanobiology. Curr. Osteoporos. Rep. 2017;15(4):318–325. doi: 10.1007/s11914-017-0373-0. PubMed DOI PMC

Huang H, Yang R, Zhou Y. Mechanobiology of periodontal ligament stem cells in orthodontic tooth movement. Stem Cells Int. 2018;2018:1–7. PubMed PMC

Masella RS, Meister M. Current concepts in the biology of orthodontic tooth movement. Am. J. Orthod. Dentofac. Orthop. 2006;129(4):458–468. doi: 10.1016/j.ajodo.2005.12.013. PubMed DOI

Jeon HH, Teixeira H, Tsai A. Mechanistic insight into orthodontic tooth movement based on animal studies: A critical review. J. Clin. Med. 2021;10(8):1733. doi: 10.3390/jcm10081733. PubMed DOI PMC

Xu H, Guan J, Jin Z, Yin C, Wu S, Sun W, et al. Mechanical force modulates macrophage proliferation via Piezo1-AKT-Cyclin D1 axis. FASEB J. 2022;36(8):00314. doi: 10.1096/fj.202200314R. PubMed DOI

Jin Y, Li J, Wang Y, Ye R, Feng X, Jing Z, et al. Functional role of mechanosensitive ion channel Piezo1 in human periodontal ligament cells. Angle Orthod. 2015;85(1):87–94. doi: 10.2319/123113-955.1. PubMed DOI PMC

Shen X, Wu W, Ying Y, Zhou L, Zhu H. A regulatory role of Piezo1 in apoptosis of periodontal tissue and periodontal ligament fibroblasts during orthodontic tooth movement. Aust. Endod. J. 2022 doi: 10.1111/aej.12721. PubMed DOI

Schröder A, Neher K, Krenmayr B, Paddenberg E, Spanier G, Proff P, et al. Impact of PIEZO1-channel on inflammation and osteoclastogenesis mediated via periodontal ligament fibroblasts during mechanical loading. Eur. J. Oral Sci. 2023;131:12913. doi: 10.1111/eos.12913. PubMed DOI

Bae C, Sachs F, Gottlieb PA. The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4. Biochemistry. 2011;50(29):6295–6300. doi: 10.1021/bi200770q. PubMed DOI PMC

Li J, Hou B, Tumova S, Muraki K, Bruns A, Ludlow MJ, et al. Piezo1 integration of vascular architecture with physiological force. Nature. 2014;515(7526):279–282. doi: 10.1038/nature13701. PubMed DOI PMC

Woo SH, Ranade S, Weyer AD, Dubin AE, Baba Y, Qiu Z, et al. Piezo2 is required for Merkel-cell mechanotransduction. Nature. 2014;509(7502):622–626. doi: 10.1038/nature13251. PubMed DOI PMC

Lu Y, Xie Y, Zhang S, Dusevich V, Bonewald LF, Feng JQ. DMP1-targeted Cre expression in odontoblasts and osteocytes. J. Dent. Res. 2007;86(4):320–325. doi: 10.1177/154405910708600404. PubMed DOI

Vijaykumar A, Ghassem-Zadeh S, Vidovic-Zdrilic I, Komitas K, Adameyko I, Krivanek J, et al. Generation and characterization of DSPP-Cerulean/DMP1-Cherry reporter mice. Genesis. 2019;57(10):23324. doi: 10.1002/dvg.23324. PubMed DOI PMC

Nottmeier C, Liao N, Simon A, Decker MG, Luther J, Schweizer M, et al. Wnt1 promotes cementum and alveolar bone growth in a time-dependent manner. J. Dent. Res. 2021;100(13):1501–1509. doi: 10.1177/00220345211012386. PubMed DOI PMC

Koehne T, Marshall RP, Jeschke A, Kahl-Nieke B, Schinke T, Amling M. Osteopetrosis, osteopetrorickets and hypophosphatemic rickets differentially affect dentin and enamel mineralization. Bone. 2013;53(1):25–33. doi: 10.1016/j.bone.2012.11.009. PubMed DOI

Nottmeier C, Decker MG, Luther J, von Kroge S, Kahl-Nieke B, Amling M, et al. Accelerated tooth movement in Rsk2-deficient mice with impaired cementum formation. Int. J. Oral Sci. 2020;12(1):35. doi: 10.1038/s41368-020-00102-4. PubMed DOI PMC

Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: Open source software for digital pathology image analysis. Sci. Rep. 2017;7(1):16878. doi: 10.1038/s41598-017-17204-5. PubMed DOI PMC

Doube M, Kłosowski MM, Arganda-Carreras I, Cordelières FP, Dougherty RP, Jackson JS, et al. BoneJ: Free and extensible bone image analysis in ImageJ. Bone. 2010;47(6):1076–1079. doi: 10.1016/j.bone.2010.08.023. PubMed DOI PMC