1. Glucocorticoids Suppress Bone Formation by Attenuating Osteoblast Differentiation via the Monomeric Glucocorticoid Receptor.
- Author
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Rauch, Alexander, Seitz, Sebastian, Baschant, Ulrike, Schilling, Arndt F., Illing, Anett, Stride, Brenda, Kirilov, Milen, Mandic, Vice, Takacz, Andrea, Schmidt-Ullrich, Ruth, Ostermay, Susanne, Schinke, Thorsten, Spanbroek, Rainer, Zaiss, Mario M., Angel, Peter E., Lerner, Ulf H., David, Jean-Pierre, Reichardt, Holger M., Amling, Michael, and Schütz, Günther
- Subjects
GLUCOCORTICOIDS ,BONE growth ,CELL differentiation ,GLUCOCORTICOID receptors ,TRANSGENIC mice ,CELL lines ,CYTOKINES ,LABORATORY mice - Abstract
Summary: 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-κB. Thus, GCs inhibit cytokines independent of GR dimerization and thereby attenuate osteoblast differentiation, which accounts, in part, for bone loss during GC therapy. [Copyright &y& Elsevier]
- Published
- 2010
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