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

作     者：Eric E Beier Tzong-Jen Sheu Emily A Resseguie Masahiko Takahata Hani A Awad Deborah A Cory-Slechta J Edward Puzas 

作者机构：Department of Environmental Medicine University of Rochester School of Medicine and Dentistry Rochester NY USA Department of Environmental and Occupational Medicine Rutgers University Piscataway NJ USA and Center for Musculoskeletal Research University of Rochester School of Medicine and Dentistry Rochester NY USA 

出 版 物：《Bone Research》 (骨研究（英文版）)

年 卷 期：2017年第5卷第2期

页      面：95-108页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100202[医学-儿科学] 10[医学] 

基　　金：supported by Public Health Service grants NIH T32 ES07026 and R01 ES012712 T32 AR053459  P01 ES011854 and P30 ES001247 

主　　题：Sclerostin prenatal negative 

摘      要：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 ***, 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.