Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. Sclerostin, a protein product of the Sost gene, is a potent inhibitor of bone formation, primarily expressed in osteocytes, which are involved in sensing mechanical signals. Recent findings suggest that sclerostin antagonizes Lrp5 receptor signaling, a key mediator of skeletal mechanotransduction, allowing osteocytes to regulate mechanotransduction by modulating their sclerostin output. This study investigated how enhanced (ulnar loading) and reduced (hindlimb unloading) loading conditions affect Sost and sclerostin expression. Ulnar loading significantly reduced Sost transcripts and sclerostin protein levels, particularly in high strain regions, while hindlimb unloading increased Sost expression in the tibia. These findings suggest that sclerostin levels are finely tuned to coordinate regional and local osteogenesis in response to mechanical stimulation, possibly by releasing local inhibition of Wnt/Lrp5 signaling. Mechanical loading reduces sclerostin, particularly in high strain regions, and this reduction correlates with increased bone formation. Conversely, hindlimb unloading increases Sost expression, indicating that sclerostin levels are regulated by mechanical strain. The study also found that mechanical loading reduces Dkk1 and sFrp1 expression, which are other Wnt signaling inhibitors. These results highlight the role of Wnt signaling in mechanically induced bone formation and provide evidence for osteocyte-specific control of mechanotransduction. Sclerostin, with its effects on osteoblast-mediated bone formation, presents an attractive target for modulating bone mass. The findings suggest that sclerostin is produced and secreted by osteocytes, and its levels are reduced in response to mechanical strain, allowing local osteoblasts to release from suppressed Wnt signaling and promote bone formation in high strain regions. The study also discusses the implications of these findings for understanding bone mechanotransduction and potential therapeutic applications.Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. Sclerostin, a protein product of the Sost gene, is a potent inhibitor of bone formation, primarily expressed in osteocytes, which are involved in sensing mechanical signals. Recent findings suggest that sclerostin antagonizes Lrp5 receptor signaling, a key mediator of skeletal mechanotransduction, allowing osteocytes to regulate mechanotransduction by modulating their sclerostin output. This study investigated how enhanced (ulnar loading) and reduced (hindlimb unloading) loading conditions affect Sost and sclerostin expression. Ulnar loading significantly reduced Sost transcripts and sclerostin protein levels, particularly in high strain regions, while hindlimb unloading increased Sost expression in the tibia. These findings suggest that sclerostin levels are finely tuned to coordinate regional and local osteogenesis in response to mechanical stimulation, possibly by releasing local inhibition of Wnt/Lrp5 signaling. Mechanical loading reduces sclerostin, particularly in high strain regions, and this reduction correlates with increased bone formation. Conversely, hindlimb unloading increases Sost expression, indicating that sclerostin levels are regulated by mechanical strain. The study also found that mechanical loading reduces Dkk1 and sFrp1 expression, which are other Wnt signaling inhibitors. These results highlight the role of Wnt signaling in mechanically induced bone formation and provide evidence for osteocyte-specific control of mechanotransduction. Sclerostin, with its effects on osteoblast-mediated bone formation, presents an attractive target for modulating bone mass. The findings suggest that sclerostin is produced and secreted by osteocytes, and its levels are reduced in response to mechanical strain, allowing local osteoblasts to release from suppressed Wnt signaling and promote bone formation in high strain regions. The study also discusses the implications of these findings for understanding bone mechanotransduction and potential therapeutic applications.