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.

Bone quality: Lead, stress and hormones

Research has provided new insight into the mechanism by which lead exposure and prenatal stress detrimentally affect bones. The adverse effects of lead exposure on bones are well documented, and evidence suggests that prenatal stress has a similar impact. The effects of both are thought to result from an excess of hormones called glucocorticoids, but the molecular pathways are unclear. J Edward Puzas from the University of Rochester, USA, and colleagues studied the effects of combined lead exposure and prenatal stress in mice. The combination reduced bone mass and strength, and affected bone development. The researchers found that the mechanism involved glucocorticoid-mediated increases in levels of sclerostin, a protein that blocks a signaling pathway important for bone formation. The finding suggests that sclerostin could be a target for treatments to improve bone health.

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