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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 and Guy Haegeman UGent, et al. (2011) FASEB JOURNAL. 25(4). p.1323-1332
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
RHEUMATOID-ARTHRITIS, SUPPRESS BONE-FORMATION, OSTEOCLAST DIFFERENTIATION, SYNOVIAL FIBROBLASTS, GENE REPRESSION, PLANT-ORIGIN, CATHEPSIN-K, MECHANISMS, CELLS, GR, osteoporosis, interleukin 11, FACTOR-KAPPA-B
journal title
FASEB JOURNAL
Faseb J.
volume
25
issue
4
pages
1323 - 1332
Web of Science type
Article
Web of Science id
000288982800021
JCR category
BIOLOGY
JCR impact factor
5.712 (2011)
JCR rank
7/84 (2011)
JCR quartile
1 (2011)
ISSN
0892-6638
DOI
10.1096/fj.10-173393
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1890324
handle
http://hdl.handle.net/1854/LU-1890324
date created
2011-08-18 15:57:31
date last changed
2013-02-27 09:09:11
@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},
  keyword      = {RHEUMATOID-ARTHRITIS,SUPPRESS BONE-FORMATION,OSTEOCLAST DIFFERENTIATION,SYNOVIAL FIBROBLASTS,GENE REPRESSION,PLANT-ORIGIN,CATHEPSIN-K,MECHANISMS,CELLS,GR,osteoporosis,interleukin 11,FACTOR-KAPPA-B},
  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},
}

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.