Mechanical force coordinates with estrogen to orchestrate alveolar bone homeostasis via PIEZO1

Healthy alveolar bone is the cornerstone for oral function and oral treatment. In the aging population, increasingly postmenopausal women requiring dental services experiences alveolar bone loss due to estrogen deficiency. Both local factors (occlusal force lose) and systemic factors (estrogen deficiency) affects their alveolar bone health, but the association remains to be clarified. Here, we identified that occlusal force is critical in maintaining alveolar bone mass and PIEZO1 coordinates mechanical force and estrogen, thus orchestrating alveolar bone homeostasis. Mechanistically, both occlusal force loss and PIEZO1 deletion may impair the osteogenesis of alveolar bone and sequentially regulate catabolic metabolism through Fas ligand (FasL)-induced osteoclastic apoptosis. PIEZO1 may promote the activity of signal transducer and activator of transcription 3 (STAT3) and estrogen receptor 1 (ESR1), which cooperatively increase Fasl transcription. This study thus revealed a cooperation between occlusal force and estrogen in maintaining alveolar bone homeostasis through a PIEZO1-STAT3/ESR1-FasL pathway. Our work supports restoration of occlusal force with dental therapies early and suggests that preventing alveolar bone loss is the major priority. PIEZO1 may serve not only as a treatment target for occlusal force loss-induced alveolar bone loss but also as a potential target for metabolic bone loss, especially in older patients.