Selective glucocorticoid receptor modulator compound A, in contrast to prednisolone, does not induce leptin or the leptin receptor in human osteoarthritis synovial fibroblasts.

Abstract

OBJECTIVE:

Glucocorticoids are powerful anti-inflammatory compounds that also induce the expression of leptin and leptin receptor (Ob-R) in synovial fibroblasts through TGF-βsignalling and Smad1/5 phosphorylation. Compound A (CpdA), a selective glucocorticoid receptor agonist, reduces inflammation in murine arthritis models and does not induce diabetes or osteoporosis, thus offering an improved risk:benefit ratio in comparison with glucocorticoids. Due to the detrimental role of leptin in OA pathogenesis, we sought to determine whether CpdA also induced leptin and Ob-R protein expression as observed with prednisolone.

METHODS:

Human synovial fibroblasts and chondrocytes were isolated from the synovium and cartilage of OA patients after joint surgery. The cells were treated with prednisolone, TGF-β1, TNF-α and/or CpdA. Levels of leptin, IL-6, IL-8, MMP-1 and MMP-3 were measured by ELISA and expression levels of Ob-R phospho-Smad1/5, phospho-Smad2, α-tubulin and glyceraldehyde 3-phosphate dehydrogenase were analysed by western blotting.

RESULTS:

CpdA, unlike prednisolone, did not induce leptin secretion or Ob-R protein expression in OA synovial fibroblasts. Moreover, CpdA decreased endogenous Ob-R expression and down-regulated prednisolone-induced leptin secretion and Ob-R expression. Mechanistically, CpdA, unlike prednisolone, did not induce Smad1/5 phosphorylation. CpdA, similarly to prednisolone, down-regulated endogenous and TNF-α-induced IL-6, IL-8, MMP-1 and MMP-3 protein secretion. The dissociative effect of CpdA was confirmed using chondrocytes with no induction of leptin secretion, but with a significant decrease in IL-6, IL-8, MMP-1 and MMP-3 protein secretion.

CONCLUSION:

CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio.

• Authors: Olivier Malaise, Biserka Relic, Florence Quesada-Calvo, Edith Charlier, Mustapha Zeddou, Sophie Neuville, Philippe Gillet, Edouard Louis, Dominique de Seny, Michel G Malaise
• Journal: Rheumatology (Oxford, England) (Rheumatology (Oxford)) Vol. 54 Issue 6 Pg. 1087-92 (Jun 2015) ISSN: 1462-0332 [Electronic] England
• PMID: 25389358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Interleukin-6
• Interleukin-8
• Leptin
• Receptors, Glucocorticoid
• Receptors, Leptin
• Smad Proteins, Receptor-Regulated
• Transforming Growth Factor beta1
• Tubulin
• Tumor Necrosis Factor-alpha
• Prednisolone
• Glyceraldehyde-3-Phosphate Dehydrogenases
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 1

Topics

• Aged
• Aged, 80 and over
• Blotting, Western
• Chondrocytes (drug effects, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Fibroblasts (drug effects, metabolism)
• Glyceraldehyde-3-Phosphate Dehydrogenases (drug effects, metabolism)
• Humans
• Interleukin-6 (metabolism)
• Interleukin-8 (drug effects, metabolism)
• Leptin (metabolism)
• Male
• Matrix Metalloproteinase 1 (drug effects, metabolism)
• Matrix Metalloproteinase 3 (drug effects, metabolism)
• Middle Aged
• Osteoarthritis (metabolism)
• Prednisolone (pharmacology)
• Receptors, Glucocorticoid (agonists)
• Receptors, Leptin (drug effects, metabolism)
• Smad Proteins, Receptor-Regulated (drug effects, metabolism)
• Synovial Membrane (drug effects, metabolism)
• Transforming Growth Factor beta1 (drug effects, metabolism)
• Tubulin (drug effects, metabolism)
• Tumor Necrosis Factor-alpha (drug effects, metabolism)