Sclerostin mediates bone response to mechanical unloading

Reduced mechanical loading leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes, which are terminally differentiated osteoblasts, have been identified as the major cells responsible for mechanotransduction. However, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. The Wnt/β-catenin pathway is implicated in bone formation. Its activation requires the interaction between Wnt, its receptor Frizzled, and a coreceptor (either low-density lipoprotein (LDL) receptor–related proteins 5 or 6 (LRP5 or LRP6)) and results in the stabilization of the transcription factor β-catenin. Wnt/β-catenin pathway activation in the osteoblast lineage favors osteoblast differentiation and osteocyte formation. Sclerostin, a secreted protein encoded by the Sost gene, binds Wnt co-receptors LRP5 and LRP6 and inhibits Wnt/β-catenin signaling. Sost is nearly exclusively expressed in osteocytes in adult bone and its expression is responsive to mechanical stimulus. However, the role of sclerostin in bone response to mechanical stress remains unknown.

The authors [1] evaluated the role of sclerostin and Wnt/β-catenin in bone response to mechanical loading. Unloading through tail suspension was associated with an increase of Sost expression and a decrease of Wnt/β-catenin signaling in femurs of adult mice. The authors generated Sost-/- mice which exhibit spontaneously increased bone mass, increased basal Wnt/β-catenin signaling in bone, and reduced osteocyte and osteoblast apoptosis. More importantly, Sost invalidation suppressed unloading-induced bone loss. Contrary to wild type mice, Sost-/- mice did not display a reduction of either matrix apposition rate nor bone formation rate in response to unload. Sost invalidation also prevented unloading-induced Wnt/β-catenin signaling inhibition.

These results suggest that mechanical loading enhances Wnt/β-catenin signaling by reducing Sost expression in osteocytes. Though, Wnt/β-catenin activity prevents bone loss by enhancing osteoblasts activity.

1. Lin C et al. J Bone Miner Res 2009;24:1651-1661.