Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor.
Development of osteoporosis severely complicates long-term glucocorticoid (GC) therapy. Using a Cre-transgenic mouse line, we now demonstrate that GCs are unable to repress bone formation in the absence of glucocorticoid receptor (GR) expression in osteoblasts as they become refractory to hormone-induced apoptosis, inhibition of proliferation, and differentiation. In contrast, GC treatment still reduces bone formation in mice carrying a mutation that only disrupts GR dimerization, resulting in bone loss in vivo, enhanced apoptosis, and suppressed differentiation in vitro. The inhibitory GC effects on osteoblasts can be explained by a mechanism involving suppression of cytokines, such as interleukin 11, via interaction of the monomeric GR with AP-1, but not NF-kappaB. Thus, GCs inhibit cytokines independent of GR dimerization and thereby attenuate osteoblast differentiation, which accounts, in part, for bone loss during GC therapy.
Tissue-specific hormone action, Leibniz Institute for Age Research, Fritz Lipmann Institute, 07745 Jena, Germany.
Alexander
A
Rauch
Sebastian
S
Seitz
Ulrike
U
Baschant
Arndt F
AF
Schilling
Anett
A
Illing
Brenda
B
Stride
Milen
M
Kirilov
Vice
V
Mandic
Andrea
A
Takacz
Ruth
R
Schmidt-Ullrich
Susanne
S
Ostermay
Thorsten
T
Schinke
Rainer
R
Spanbroek
Mario M
MM
Zaiss
Peter E
PE
Angel
Ulf H
UH
Lerner
Jean-Pierre
JP
David
Holger M
HM
Reichardt
Michael
M
Amling
Günther
G
Schütz
Jan P
JP
Tuckermann
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019281:Dimerization; D005938:Glucocorticoids / Q000633:toxicity*; D017370:Interleukin-11 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D005938:Glucocorticoids; D017370:Interleukin-11; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1