ECTS2014 Poster Presentations Steroid hormones and receptors (4 abstracts)
Novel mechanisms of action and new target genes of the glucocorticoid receptor in inflammatory bone disease and bone loss
Ulrike Baschant 1, , Mubashir Ahmad 1, , Mascha Koenen 1 , Jeanette Knoll 1, , Stephan Culemann 2, , Sebastian Schauer 1 , Kerstin Bauer 1 , Stephanie Wittig-Blaich 1 , Alexander Rauch 2 , Gehrhard Krönke 4 , Anne Dudeck 5 , Jean-Pierre David 6 , Martina Rauner 3 , Markus Seibel 7 , Aspasia Ploubidou 2 , Hong Zhou 7 , Lorenz Hofbauer 3 & Jan Tuckermann 1,
1Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany; 2FLI, Leibniz Institute for Age Research, Jena, Germany; 3Endocrinologie, Diabetes und Knochenerkrankungen, Medizinische
Klinik 3, Universitätsklinikum Dresden, Dresden, Germany; 4Medical Clinic III, University of Erlangen, Erlangen, Germany; 5Institute of Immunology, Dresden, Germany; 6Institute for Osteology and
Biomechanics, University Clinic Eppendorf, Hamburg, Germany;
7Bone Research Program, ANZAC Research Institute, University of Sydney, Sidney, Australia.
Glucocorticoids (GCs) are widely used to treat chronic inflammatory diseases such as rheumatoid (RA) and lead to multiple side effects including glucocorticoid induced osteoporosis (GIO). Our work challenges the dogma that transrepression of pro-inflammatory genes by the glucocorticoid receptor (GR) is solely responsible for reducing inflammation, whereas transactivation of genes is causing side effects.
Using conditional and function selective mutant mice for the GR we recently revealed that transrepression of genes by the GR is not sufficient to suppress inflammation in mouse models of arthritis in vivo (PNAS 2011 108: 19317). In contrast transactivation of anti-inflammatory genes by GR dimerization is absolutely required, since mice carrying a GR with disturbed dimerization interface do not respond to GCs to reduce inflammation in antigen-induced arthritis and K/BxN serum induced arthritis. Whereas in antigen-induced arthritis GR function in T cells is essential we surprisingly discovered that in K/BxN serum induced arthritis GR expression in non-hematopoietic cells suppress inflammation.
In contrast to suppression of inflammation, the induction of GIO, the most secondary osteoporosis and a major side effect of steroid therapy, depends on GR mediated transrepression of genes mainly in osteoblasts (Cell Metabolism 2010 11: 517). Here mice with attenuated GR dimerization reacted completely normal in inhibition of bone formation and decrease of osteoblast differentiation. By setting up an siRNA screen in pre-osteoblasts we functionally characterized novel GR target genes involved in osteoblast differentiation, which could serve as novel drug targets to avoid GIO.
Our work defines new criteria for novel GR modifying compounds and provides new GR target genes that can be addressed to optimize anti-inflammatory therapy by avoiding deleterious effects on bone.
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Bone Abstracts
ISSN 2052-1219 (online)
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