Piezo1 Protects Against Inflammatory Bone Loss via a Unique Ca²⁺- Independent Mechanism in Osteoclasts

Satoru Shindo^1*Shin Nakamura¹Avery Hawthorne¹Alireza Heidari¹Maria Rita Pastore¹Motoki Okamoto¹Maiko Suzuki¹Manuel Salinas²Takumi Memida¹Dmitriy Minond³Alexander Bontempo¹Mark Cayabyab¹Yingzi Yang⁴Janet L Crane⁵Maria Hernandez¹Saynur Vardar¹Patrick Hardigan⁶Xiaozhe Han¹Steven Kaltman¹Toshihisa Kawai^1*

• ¹Nova Southeastern University College of Dental Medicine, Fort Lauderdale, United States
• ²Nova Southeastern University College of Computing and Engineering, Fort Lauderdale, United States
• ³Nova Southeastern University Barry and Judy Silvermen College of Pharmacy, Fort Lauderdale, United States
• ⁴Harvard School of Dental Medicine Department of Developmental Biology, Boston, United States
• ⁵Johns Hopkins Medicine Department of Orthopaedic Surgery, Baltimore, United States
• ⁶Nova Southeastern University Dr Kiran C Patel College of Allopathic Medicine, Fort Lauderdale, United States

Bone integrity is critically maintained by mechanical stimulation, and its absence—whether due to disuse osteoporosis or periodontitis—accelerates osteoclast-mediated bone resorption. While Piezo1 is a well-characterized mechanosensitive ion channel in various cell types, its functional role in osteoclast lineage cells has remained unclear. Here, we identified Piezo1, which was previously thought not to function as a mechanosensor in pre-osteoclasts (pre-OCs), as an important mechanosensor that is selectively expressed and functions in pre-OCs. Mechanistically, Piezo1 activation inhibits NFATc1, the master transcriptional regulator of OC-genesis, through a novel, Ca²⁺-independent pathway involving PP2A-mediated dephosphorylation of Akt, rather than the canonical Ca²⁺-calcineurin axis. In healthy periodontal bone, Piezo1 acts as a molecular brake that restrains RANKL-induced osteoclast differentiation, preserving bone under normal mechanical loading conditions. However, this safeguard is compromised in periodontitis, where reduced mechanical force impairs Piezo1 function, leading to pathological bone resorption. Remarkably, pharmacological activation of Piezo1 using the small molecule agonist Yoda1 restores this anti-resorptive signaling pathway, even in the absence of mechanical input, and effectively prevents inflammatory bone loss. These findings not only redefine the role of Piezo1 in osteoclast biology but also establish a previously unrecognized Piezo1–PP2A–Akt axis as a critical regulatory mechanism in bone homeostasis. Moreover, our study provides a rationale for targeting Piezo1 pharmacologically to mimic mechanical cues and suppress OC-genesis, offering a novel therapeutic approach for preventing pathogenic bone loss, such as periodontitis, rheumatoid arthritis, and osteoporosis.