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.
Highlights
Stress and sustained elevation of stress-related hormones like cortisol, which are associated with a variety of disorders and diseases are more prevalent among communities with low socioeconomic status.[1,2,3] Elevated stress can occur at any period throughout life
Effects of prenatal stress (PS) and Pb on bone mass Exposure to PS had a minimal effect on trabecular bone quality in male offspring at 8 months (Figure 1)
The effect of GCs on osteoblasts and bone mineralization are convoluted, exhibiting both negative and positive effects depending on the steroid concentration, cell differentiation state, and species
Summary
Stress and sustained elevation of stress-related hormones like cortisol, which are associated with a variety of disorders and diseases are more prevalent among communities with low socioeconomic status.[1,2,3] Elevated stress can occur at any period throughout life. Glucocorticoids (GC) are synthesized and secreted by the adrenal glands and have substantial impact on the physiological functioning of several body systems, including metabolism, adaptation to stress events and modulation of host defense, the later being important in consideration of therapeutic administration of GC. The signaling axis of GC consists of the hypothalamic-pituitaryadrenal (HPA) axis and is influenced by a multitude of
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