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Osteocytes are well evidenced to be the major mechanosensor in bone, responsible for sending signals to the effector cells (osteoblasts and osteoclasts) that carry out bone formation and resorption. Consistent with this hypothesis, it has been shown that osteocytes release various soluble factors (e.g. transforming growth factor-β, nitric oxide, and prostaglandins) that influence osteoblastic and osteoclastic activities when subjected to a variety of mechanical stimuli, including fluid flow, hydrostatic pressure, and mechanical stretching. Recently, low-magnitude, high-frequency (LMHF) vibration (e.g., acceleration less than < 1 × g, where g = 9.81 m/s2, at 20–90 Hz) has gained much interest as studies have shown that such mechanical stimulation can positively influence skeletal homeostasis in animals and humans. Although the anabolic and anti-resorptive potential of LMHF vibration is becoming apparent, the signaling pathways that mediate bone adaptation to LMHF vibration are unknown. We hypothesize that osteocytes are the mechanosensor responsible for detecting the vibration stimulation and producing soluble factors that modulate the activity of effector cells. Hence, we applied low-magnitude (0.3 × g) vibrations to osteocyte-like MLO-Y4 cells at various frequencies (30, 60, 90 Hz) for 1 h. We found that osteocytes were sensitive to this vibration stimulus at the transcriptional level: COX-2 maximally increased by 344% at 90 Hz, while RANKL decreased most significantly (−55%, p < 0.01) at 60 Hz. Conditioned medium collected from the vibrated MLO-Y4 cells attenuated the formation of large osteoclasts (≥ 10 nuclei) by 36% (p < 0.05) and the amount of osteoclastic resorption by 20% (p = 0.07). The amount of soluble RANKL (sRANKL) in the conditioned medium was found to be 53% lower in the vibrated group (p < 0.01), while PGE2 release was also significantly decreased (−61%, p < 0.01). We conclude that osteocytes are able to sense LMHF vibration and respond by producing soluble factors that inhibit osteoclast formation.