Shindo, S.; Nakamura, S.; Hawthorne, A.; Heidari, A.; Pastore, M. R.; Okamoto, M.; Suzuki, M.; Salinas, M.; Minond, D.; Bontempo, A.; Cayabyab, M.; Yang, Y.; Crane, J. L.; Hernandez, M.; Vardar, S.; Hardigan, P.; Han, X.; Kaltman, S.; Kawai, T.

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 Ca2+ 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 Ca2+/calcineurin/NFAT axis upregulates NFATc1 activation in pre-OCs. Interestingly, Piezo1-elicited Ca2+ 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+/phospho-Akt+ 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.