Sclerostin activity plays a key role in the negative effect of glucocorticoid signaling on osteoblast function in mice

Abstract

Stress during prenatal development is correlated with detrimental cognitive and behavioral outcomes in offspring. However, the long-term impact of prenatal stress (PS) and disrupted glucocorticoid signaling on bone mass and strength is not understood. In contrast, the detrimental effect of lead (Pb) on skeletal health is well documented. As stress and Pb act on common biological targets via glucocorticoid signaling pathways and co-occur in the environment, this study first sought to assess the combined effect of stress and Pb on bone quality in association with alterations in glucocorticoid signaling. Bone parameters were evaluated using microCT, histomorphometry, and strength determination in 8-month-old male mouse offspring subjected to PS on gestational days 16 and 17, lifetime Pb exposure (100 p.p.m. Pb in drinking water), or to both. Pb reduced trabecular bone mass and, when combined with PS, Pb unmasked an exaggerated decrement in bone mass and tensile strength. Next, to characterize a mechanism of glucocorticoid effect on bone, prednisolone was implanted subcutaneously (controlled-release pellet, 5 mg·kg−1 per day) in 5-month-old mice that decreased osteoblastic activity and increased sclerostin and leptin levels. Furthermore, the synthetic glucocorticoid dexamethasone alters the anabolic Wnt signaling pathway. The Wnt pathway inhibitor sclerostin has several glucocorticoid response elements, and dexamethasone administration to osteoblastic cells induces sclerostin expression. Dexamethasone treatment of isolated bone marrow cells decreased bone nodule formation, whereas removal of sclerostin protected against this decrement in mineralization. Collectively, these findings suggest that bone loss associated with steroid-induced osteoporosis is a consequence of sclerostin-mediated restriction of Wnt signaling, which may mechanistically facilitate glucocorticoid toxicity in bone.

Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mice offspring

“…week-old mice offspring. Our finding is supported by a recent report that PDE at GD 16-17 induced decreased bone mass and biomechanical strength in adult mice offspring [23]. Furthermore, we observed a notable decrease in both osteoblasts and osteoclasts in femoral metaphysis of mice offspring after PDE, indicating a decreased bone modeling and remodeling induced by PDE.…”

Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mice offspring

“…In the present study, the data clearly indicate that PDE at 1.2 mg/kg/day during GD 12-14 induces low bone mass in 12-week-old mice offspring. Our nding is supported by a recent report that PDE at GD 16-17 induces decreased bone mass and biomechanical strength in adult mice offspring [30]. Furthermore, we observed a notable decrease in both osteoblasts and osteoclasts in femoral metaphysis of female mice offspring after PDE, indicating a decreased bone modeling and remodeling induced by PDE.…”

Active Cushing syndrome patients have increased ectopic fat deposition and bone marrow fat content compared to cured patients and healthy subjects: a pilot 1H-MRS study

“…Peroxisome proliferator-activated receptor-gamma (PPAR-γ), which represses osteogenic transcription factors (runt-related transcription factor 2 and osterix) and stimulates expression of adipogenic genes in bone marrow, was already found to be modulated by hypercortisolism in VAT (28). Glucocorticoids can also dysregulate Wnt/β catenin signaling, which is a key regulator of the two lineages, by stimulating Wnt antagonists (sclerostin and dickkopf-1), as shown in studies conducted in humans and mice (29,30,31).…”