Sato, Amy Y.Cregor, MeloneyDelgado-Calle, JesusCondon, Keith W.Allen, Matthew R.Peacock, MunroPlotkin, Lilian I.Bellido, Teresita2023-03-152023-03-152016-10Sato AY, Cregor M, Delgado-Calle J, et al. Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin. J Bone Miner Res. 2016;31(10):1791-1802. doi:10.1002/jbmr.2869https://hdl.handle.net/1805/31909Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost-/- mice. The high bone mass exhibited by Sost-/- mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost-/- mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/β-catenin pathway by decreasing the expression of genes associated with both anti-catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost-/- mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β-catenin signaling.en-USPublisher PolicyCorticosteroidsOsteoporosisGenetic animal modelsMolecular pathwaysWnt signaling pathwayArticle