Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis.
Glucocorticoid-induced osteoporosis may be at least in part due to the increased apoptosis of osteocytes. To study the role of osteocyte apoptosis in glucocorticoid-induced osteoporosis, we isolated primary osteocytes from murine calvaria for the analysis of the effects of dexamethasone in in vitro culture. The cells were identified by morphology, cytochemical staining, immunocytochemical staining and mRNA expression of phosphate-regulating gene with homology to endopeptidases on the X chromosome (PHEX) and sclerosteosis/van Buchem disease gene (SOST). We found that dexamethasone induced osteocyte apoptosis in a dose-dependent manner. A glucocorticoid receptor antagonist, mifepristone (RU486), suppressed dexamethasone-induced osteocyte apoptosis, suggesting that it was mediated by glucocorticoid receptor. Immunocytochemical stainings showed that glucocorticoid receptors are present in primary osteocytes, and they were translocated to nuclei after the exposure to dexamethasone. Addition of estrogen prevented glucocorticoid receptor translocation into nuclei. Corresponding antiapoptotic effects in primary osteocytes were also seen after the pretreatment of primary osteocytes with a picomolar concentration of estrogen. The pure antiestrogen ICI 182,780 inhibited estrogen effect on apoptosis induced by dexamethasone. These data suggest that glucocorticoid receptors play an important role in glucocorticoid-induced osteocyte apoptosis. Most importantly, estrogen has a protective effect against osteocyte apoptosis. To conclude, the mechanism of glucocorticoid-induced osteoporosis may be due to the apoptosis of osteocytes, which can be opposed by estrogen.
Gu
G
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Department of Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland.
Hentunen
T A
TA
Nars
M
M
Härkönen
P L
PL
Väänänen
H K
HK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D000077267:Fulvestrant; D005938:Glucocorticoids / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D000077267:Fulvestrant; D015735:Mifepristone; D004958:Estradiol; D003907:Dexamethasone