Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor.
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Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. / Rauch, Alexander; Seitz, Sebastian; Baschant, Ulrike; Schilling, Arndt; 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; Schütz, Günther; Tuckermann, Jan P.
in: CELL METAB, Jahrgang 11, Nr. 6, 6, 2010, S. 517-531.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor.
AU - Rauch, Alexander
AU - Seitz, Sebastian
AU - Baschant, Ulrike
AU - Schilling, Arndt
AU - Illing, Anett
AU - Stride, Brenda
AU - Kirilov, Milen
AU - Mandic, Vice
AU - Takacz, Andrea
AU - Schmidt-Ullrich, Ruth
AU - Ostermay, Susanne
AU - Schinke, Thorsten
AU - Spanbroek, Rainer
AU - Zaiss, Mario M
AU - Angel, Peter E
AU - Lerner, Ulf H
AU - David, Jean-Pierre
AU - Reichardt, Holger M
AU - Amling, Michael
AU - Schütz, Günther
AU - Tuckermann, Jan P
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Mice, Knockout
KW - Apoptosis
KW - Cell Differentiation
KW - Osteogenesis drug effects
KW - Osteoblasts cytology
KW - Dimerization
KW - Glucocorticoids toxicity
KW - Interleukin-11 metabolism
KW - Receptors, Glucocorticoid genetics
KW - Transcription Factor AP-1 metabolism
KW - Animals
KW - Mice
KW - Mice, Knockout
KW - Apoptosis
KW - Cell Differentiation
KW - Osteogenesis drug effects
KW - Osteoblasts cytology
KW - Dimerization
KW - Glucocorticoids toxicity
KW - Interleukin-11 metabolism
KW - Receptors, Glucocorticoid genetics
KW - Transcription Factor AP-1 metabolism
M3 - SCORING: Zeitschriftenaufsatz
VL - 11
SP - 517
EP - 531
JO - CELL METAB
JF - CELL METAB
SN - 1550-4131
IS - 6
M1 - 6
ER -