Osteocytes function as critical regulators of bone homeostasis by coordinating the functions of osteoblasts and osteoclasts, and are constantly exposed to mechanical force. However, the molecular mechanism underlying the mechanical signal transduction in osteocytes is not well understood. Here, we found that Yoda1, a selective Piezo1 agonist, increased intracellular calcium mobilization and dose-dependently decreased the expression of Sost (encoding Sclerostin) in the osteocytic cell line IDG-SW3. We also demonstrated that mechanical stretch of IDG-SW3 suppressed Sost expression, a result which was abrogated by treatment with the Piezo1 inhibitor GsMTx4, and the deficiency of Piezo1. Furthermore, the suppression of Sost expression was abolished by treatment with an Akt inhibitor. Taken together, these results indicate that the activation of the Piezo1-Akt pathway in osteocytes is required for mechanical stretch-induced downregulation of Sost expression. (C) 2019 Elsevier Inc. All rights reserved.