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2017 ; 5
(ä): 17013
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Sclerostin activity plays a key role in the negative effect of glucocorticoid
signaling on osteoblast function in mice
#MMPMID28529816
Beier EE
; Sheu TJ
; Resseguie EA
; Takahata M
; Awad HA
; Cory-Slechta DA
; Puzas JE
Bone Res
2017[]; 5
(ä): 17013
PMID28529816
show ga
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.