The study investigates the regulation of Sost/sclerostin, a potent inhibitor of bone formation, under mechanical loading conditions. Sclerostin is primarily expressed in osteocytes, which are thought to sense and initiate mechanical signaling. The authors hypothesized that enhanced mechanical loading would reduce sclerostin levels, particularly in high-strain regions, while reduced loading would increase sclerostin expression. Using ulnar loading and hindlimb unloading models in mice, they found that sclerostin protein levels were significantly reduced by ulnar loading, with a greater reduction in high-strain regions. Conversely, hindlimb unloading increased Sost expression in the tibia. These findings suggest that sclerostin levels are finely tuned by osteocytes to coordinate regional and local osteogenesis in response to mechanical stimulation, possibly by modulating Wnt/Lrp5 signaling. The study highlights the role of Wnt signaling in mechanotransduction and provides evidence for osteocyte-specific control of this process.The study investigates the regulation of Sost/sclerostin, a potent inhibitor of bone formation, under mechanical loading conditions. Sclerostin is primarily expressed in osteocytes, which are thought to sense and initiate mechanical signaling. The authors hypothesized that enhanced mechanical loading would reduce sclerostin levels, particularly in high-strain regions, while reduced loading would increase sclerostin expression. Using ulnar loading and hindlimb unloading models in mice, they found that sclerostin protein levels were significantly reduced by ulnar loading, with a greater reduction in high-strain regions. Conversely, hindlimb unloading increased Sost expression in the tibia. These findings suggest that sclerostin levels are finely tuned by osteocytes to coordinate regional and local osteogenesis in response to mechanical stimulation, possibly by modulating Wnt/Lrp5 signaling. The study highlights the role of Wnt signaling in mechanotransduction and provides evidence for osteocyte-specific control of this process.