Glucocorticoids Suppress Bone Formation by Attenuating Osteoblast Differentiation via the Monomeric Glucocorticoid Receptor
| Autor: | Jan Tuckermann, Ulf H. Lerner, Rainer Spanbroek, Brenda D. Stride, Mario M. Zaiss, Milen Kirilov, Holger M. Reichardt, Günther Schütz, Jean-Pierre David, Ulrike Baschant, Michael Amling, Anett Illing, Thorsten Schinke, Arndt F. Schilling, Alexander Rauch, Ruth Schmidt-Ullrich, Vice Mandic, Susanne Ostermay, Andrea Takacz, Sebastian Seitz, Peter Angel |
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| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Physiology Cellular differentiation HUMDISEASE Apoptosis 030209 endocrinology & metabolism Biology Mice 03 medical and health sciences Receptors Glucocorticoid 0302 clinical medicine Glucocorticoid receptor Osteogenesis In vivo Internal medicine medicine Animals Receptor Glucocorticoids Molecular Biology 030304 developmental biology Mice Knockout 0303 health sciences Osteoblasts Cell Differentiation Osteoblast Cell Biology Interleukin-11 Cell biology Transcription Factor AP-1 Interleukin 11 medicine.anatomical_structure Endocrinology Dimerization Glucocorticoid medicine.drug |
| Zdroj: | Cell Metabolism. 11:517-531 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2010.05.005 |
| Popis: | SummaryDevelopment 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-κB. Thus, GCs inhibit cytokines independent of GR dimerization and thereby attenuate osteoblast differentiation, which accounts, in part, for bone loss during GC therapy. |
| Databáze: | OpenAIRE |
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