{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T09:59:53Z","timestamp":1784627993633,"version":"3.55.0"},"posted":{"date-parts":[[2024,9,5]]},"group-title":"Cell Biology","reference-count":107,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mechanical stimulus to the multicellular bone unit (MBU) plays a key role in normal bone remodeling, whereas disuse osteoporosis, for example, represents loss of bone owing to lack of mechanical stresses. The analogy can be applied to a variety of pathogenic bone lytic complications, including periodontitis, in which local mechanical stress appears to be diminished. The activation of mechanosensitive Piezo1 Ca\n                  <jats:sup>2+<\/jats:sup>\n                  channel expressed by osteoblasts and osteocytes in the MBU elicits the osteogenic signals in those cells. However, since osteoclast (OC)-specific Piezo1-gene knockout mice showed no skeletal phenotype, it has been assumed that Piezo1 might not play any role in OC-mediated bone remodeling. Here, however, we showed that mechanical stimulation of Piezo1 expressed on preosteoclasts (pre-OCs) downmodulates OC formation and, hence, bone resorptive activity in periodontitis, accompanied by significantly reduced expression of NFATc1, a master transcription factor for RANKL-induced OC-genesis. We know that the Ca\n                  <jats:sup>2+<\/jats:sup>\n                  \/calcineurin\/NFAT axis upregulates NFATc1 activation in pre-OCs. Interestingly, Piezo1-elicited Ca\n                  <jats:sup>2+<\/jats:sup>\n                  influx did not affect NFATc1 expression. Instead, PP2A-mediated dephosphorylation of Akt downregulated NFATc1 in Piezo1-activated pre-OCs. However, systemic administration with Yoda1, a Piezo1 chemical agonist, or local injection of PP2A agonist, significantly downregulated the bone resorption induced in a mouse model of periodontitis, together with reduced numbers of TRAP\n                  <jats:sup>+<\/jats:sup>\n                  \/phospho-Akt\n                  <jats:sup>+<\/jats:sup>\n                  pre-OCs in local bone. These results suggest that mechanosensing by Piezo1 expressed on pre-OCs can downmodulate the RANKL-induced OC-genesis via the PP2A\/Akt-dephosphorylation pathway, but that such Piezo1-mediated downregulation of bone resorption is attenuated in periodontitis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    The mechanosensitive Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel Piezo1 plays important regulatory roles in a variety of cellular activities. RANKL-mediated OC-genesis requires permissive co-stimulatory signal from ITAM receptors, such as OSCAR and TREM2, to trigger the calcineurin\/calmodulin signaling axis via Ca\n                    <jats:sup>2+<\/jats:sup>\n                    oscillation, thereby upregulating NFATc1 expression. Activation of Piezo1 remarkably suppressed RANKL-induced NFATc1 activation which, in turn, reduced OC-genesis. Such mechanical activation of Piezo1 expressed on pre-OCs induced intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx. Nonetheless, PP2A-mediated dephosphorylation of Akt, not the calcineurin\/calmodulin pathway, suppressed NFATc1 in RANKL-elicited OC-genesis and resultant bone resorption, both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These results indicate that mechanostress applied to pre-OCs can downregulate pathogenic OC-genesis and that Piezo1, as the mediator, is a novel molecular target for the development of anti-osteolytic therapies.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.09.04.611049","type":"posted-content","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T11:30:46Z","timestamp":1725535846000},"source":"Crossref","is-referenced-by-count":5,"title":["Mechanosensing by Piezo1 regulates osteoclast differentiation via PP2A-Akt axis in periodontitis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0478-9363","authenticated-orcid":false,"given":"Satoru","family":"Shindo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Rawas-Qalaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Heidari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Pastore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiko","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Salinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitriy","family":"Minond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Bontempo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Cayabyab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet L","family":"Crane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saynur","family":"Vardar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Hardigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhe","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Kaltman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihisa","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"14","key":"2024090900400497000_2024.09.04.611049v1.1","first-page":"216","article-title":"Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions","volume":"2000","year":"1997","journal-title":"Periodontology"},{"key":"2024090900400497000_2024.09.04.611049v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-051X.1991.tb02310.x"},{"key":"2024090900400497000_2024.09.04.611049v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2016.08.008"},{"key":"2024090900400497000_2024.09.04.611049v1.4","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01399"},{"issue":"11","key":"2024090900400497000_2024.09.04.611049v1.5","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nrrheum.2012.153","article-title":"Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment","volume":"8","year":"2012","journal-title":"Nature reviews. 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