Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor
Autor/innen
- A. Rauch
- S. Seitz
- U. Baschant
- A.F. Schilling
- A. Illing
- B. Stride
- M. Kirilov
- V. Mandic
- A. Takacz
- R. Schmidt-Ullrich
- S. Ostermay
- T. Schinke
- R. Spanbroek
- M.M. Zaiss
- P.E. Angel
- U.H. Lerner
- J.P. David
- H.M. Reichardt
- M. Amling
- G. Schuetz
- J.P. Tuckermann
Journal
- Cell Metabolism
Quellenangabe
- Cell Metab 11 (6): 517-531
Zusammenfassung
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.