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Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor

Item Type:Article
Title:Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor
Creators Name:Rauch, A. and Seitz, S. and Baschant, U. and Schilling, A.F. and Illing, A. and Stride, B. and Kirilov, M. and Mandic, V. and Takacz, A. and Schmidt-Ullrich, R. and Ostermay, S. and Schinke, T. and Spanbroek, R. and Zaiss, M.M. and Angel, P.E. and Lerner, U.H. and David, J.P. and Reichardt, H.M. and Amling, M. and Schuetz, G. and Tuckermann, J.P.
Abstract: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.
Keywords:Apoptosis, Cell Differentiation, Dimerization, Glucocorticoids, Interleukin-11, Osteoblasts, Osteogenesis, Glucocorticoid Receptors, Transcription Factor AP-1, Animals, Mice
Source:Cell Metabolism
ISSN:1550-4131
Publisher:Cell Press
Volume:11
Number:6
Page Range:517-531
Date:9 June 2010
Official Publication:https://doi.org/10.1016/j.cmet.2010.05.005
PubMed:View item in PubMed

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