title: An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation.
abstract: Glucocorticoids (GCs) are in widespread use to treat inflammatory bone diseases, such as rheumatoid arthritis (RA). Their anti-inflammatory efficacy, however, is accompanied by deleterious effects on bone, leading to GC-induced osteoporosis (GIO). These effects include up-regulation of the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio to promote bone-resorbing osteoclasts and include inhibition of bone-forming osteoblasts. We previously identified suppression of osteoblast differentiation by the monomer glucocorticoid receptor (GR) via the inhibition of Il11 expression as a crucial mechanism for GIO. Here we show that the GR-modulating substance compound A (CpdA), which does not induce GR dimerization, still suppresses proinflammatory cytokines in fibroblast-like synovial cells from patients with RA and in osteoblasts. In contrast to the full GR agonist dexamethasone, it does not unfavorably alter the RANKL/OPG ratio and does not affect Il11 expression and subsequent STAT3 phosphorylation in these cells. Notably, while dexamethasone inhibits osteoblast differentiation, CpdA does not affect osteoblast differentiation in vitro and in vivo. We describe here for the first time that selective GR modulators can act against inflammation, while not impairing osteoblast differentiation.
authors.affiliation: Group of Tissue-Specific Hormone Action, Fritz Lipmann Institute, Leibniz Institute for Age Research, Jena, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rauch
authors.forename: Valerie
authors.initials: V
authors.lastname: Gossye
authors.forename: Debby
authors.initials: D
authors.lastname: Bracke
authors.forename: Elien
authors.initials: E
authors.lastname: Gevaert
authors.forename: Peggy
authors.initials: P
authors.lastname: Jacques
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Beneden
authors.forename: Bernard
authors.initials: B
authors.lastname: Vandooren
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001388:Aziridines / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects; D010024:Osteoporosis / Q000139:chemically induced*; D053244:Osteoprotegerin / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001388:Aziridines; D005938:Glucocorticoids; D017370:Interleukin-11; C497713:NR3C1 protein, human; D053244:Osteoprotegerin; D010936:Plant Extracts; D053245:RANK Ligand; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone