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An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation

Alexander Rauch, Valerie Gossye (UGent) , Debby Bracke (UGent) , Elien Gevaert (UGent) , Peggy Jacques (UGent) , Katrien Van Beneden (UGent) , BERNARD VANDOOREN (UGent) , Martina Rauner, Lorenz C Hofbauer, Guy Haegeman (UGent) , et al.
(2011) FASEB JOURNAL. 25(4). p.1323-1332
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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-kappa B 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.
Keywords
RHEUMATOID-ARTHRITIS, SUPPRESS BONE-FORMATION, OSTEOCLAST DIFFERENTIATION, SYNOVIAL FIBROBLASTS, GENE REPRESSION, PLANT-ORIGIN, CATHEPSIN-K, MECHANISMS, CELLS, GR, osteoporosis, interleukin 11, FACTOR-KAPPA-B

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Citation

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Chicago
Rauch, Alexander, Valerie Gossye, Debby Bracke, Elien Gevaert, Peggy Jacques, Katrien Van Beneden, BERNARD VANDOOREN, et al. 2011. “An Anti-inflammatory Selective Glucocorticoid Receptor Modulator Preserves Osteoblast Differentiation.” Faseb Journal 25 (4): 1323–1332.
APA
Rauch, A., Gossye, V., Bracke, D., Gevaert, E., Jacques, P., Van Beneden, K., VANDOOREN, B., et al. (2011). An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation. FASEB JOURNAL, 25(4), 1323–1332.
Vancouver
1.
Rauch A, Gossye V, Bracke D, Gevaert E, Jacques P, Van Beneden K, et al. An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation. FASEB JOURNAL. 2011;25(4):1323–32.
MLA
Rauch, Alexander, Valerie Gossye, Debby Bracke, et al. “An Anti-inflammatory Selective Glucocorticoid Receptor Modulator Preserves Osteoblast Differentiation.” FASEB JOURNAL 25.4 (2011): 1323–1332. Print.
@article{1890324,
  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-kappa B 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.},
  author       = {Rauch, Alexander and Gossye, Valerie and Bracke, Debby and Gevaert, Elien and Jacques, Peggy and Van Beneden, Katrien and VANDOOREN, BERNARD and Rauner, Martina and Hofbauer, Lorenz C and Haegeman, Guy and Elewaut, Dirk and Tuckermann, Jan P and De Bosscher, Karolien},
  issn         = {0892-6638},
  journal      = {FASEB JOURNAL},
  language     = {eng},
  number       = {4},
  pages        = {1323--1332},
  title        = {An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation},
  url          = {http://dx.doi.org/10.1096/fj.10-173393},
  volume       = {25},
  year         = {2011},
}
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