Session Type: Abstract Submissions (ACR)
Leptin is generally considered detrimental in osteoarthritis (OA) as it can induce IL-8 in synovial fibroblasts (SF) and matrix metalloproteinases in chondrocytes. We recently showed that SF themselves were able to produce leptin and express leptin receptor (Ob-R) in vitro, strongly induced by glucocorticoid (GC) prednisolone, through TGF-β pathway and Smad1/5 phosphorylation (Stem Cell Dev 2012; 21: 1948-55). It is generally believed that transrepression of transcription factors by monomeric GC receptor (GR) is associated with GC anti-inflammatory properties, whereas side-effects (mellitus diabetes, lipid abnormalities, osteoporosis) would be mostly resulting in GR dimer-dependent transactivation. Compound A (CpdA), a plant-derived phenyl aziridine selective GR agonist, is efficient to reduce inflammation in a murine arthritis model and does not induce mellitus diabetes nor osteoporosis, offering a better benefit/risk ratio than GC. The aim of this study is to determine, in human OA SF and dedifferentiated chondrocytes (DDC), whether CpdA, as prednisolone, is leptin and Ob-R inducer.
Methods: Human SF and chondrocytes were isolated from OA patients during knee or hip surgery. Cells were treated with prednisolone (1 μM), TNF-α (10 ng/ml) and/or CpdA (1, 5 or 10 μM). ELISA measured leptin and IL-6 production in culture supernatant. Ob-R, GR, TGF-βRII, phospho-Smad1/5, phospho-Smad2, Smad1, Smad2, GILZ and α-tubulin were analyzed in total cell extracts by Western Blot.
1. Like prednisolone, CpdA down-regulated endogenous and TNF-α-induced IL-6 secretion by SF and DDC in a dose-dependent manner, supporting its anti-inflammatory action. 2. By contrast to prednisolone, CpdA did not induce leptin and further decreased endogenous Ob-R expression in a dose-dependent manner in the same cells. Moreover, unlike prednisolone, CpdA did not induce TGF-βRII expression nor Smad1/5 phosphorylation and did not reduce Smad2 phosphorylation. Lastly, also opposite to prednisolone, CpdA poorly induced GR degradation and did not induce GILZ expression.
Conclusion: Unlike prednisolone, CpdA, a dissociative glucocorticoid receptor agonist, did not induce leptin nor Ob-R in human OA SF and in DDC and could even decrease Ob-R expression. As leptin favors osteoblastic differentiation of mesenchymal stem cells, our findings might explain why CpdA also fails to induce such a differentiation. Leptin is a new target where dissociative properties of CpdA can apply.
D. de Seny,
M. G. Malaise,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/glucocorticoid-receptor-modulator-compound-a-does-not-induce-leptin-in-human-osteoarthritic-synovial-fibroblasts-and-in-dedifferentiated-chondrocytes/