Background/Purpose:

Osteoarthritis (OA) is a metabolic disorder for which leptin is playing a catabolic role on cartilage. In mice, obesity due to impaired leptin did not cause OA. In vitro, we have previously shown that OA synovial fibroblasts (SF) produced leptin, hypothesizing that they were also able to contribute to intra-articular levels of leptin. The glucocorticoid prednisolone strongly induced leptin and leptin receptor (Ob-R), suggesting a deleterious involvement in the metabolic component of OA.

Aldosterone, a mineralocorticoid, is found in OA synovial fluid and is involved in systemic metabolic regulation. First, we will study the mineralocorticoid’s influence on leptin and Ob-R expressions, and determine whether leptin and Ob-R are glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) dependent.

Glucocorticoid-Induced Leucine Zipper (GILZ) protein, induced by glucocorticoids, is an anti-inflammatory mediator in inflammatory models. Links with leptin are unknown, but GILZ’s overexpression decreases adipogenic and enhances osteogenic differentiation, two processes associated to leptin. We will study GILZ’s involvement in leptin expression.

Methods:

Human SF were isolated from OA patients during knee surgery and treated with glucocorticoid (prednisolone), mineralocorticoid (aldosterone), GR agonist (Compound A, CpdA), GR antagonist (mifepristone), MR antagonists (eplerenone, spironolactone), TNF-α and TGF-β. SF were transfected with shRNA lentiviruses for GILZ and GR silencing. ELISA measured leptin and IL-6. Ob-R, GR, GILZ and GAPDH were analyzed by Western Blot.

Results:

(1)  Prednisolone and aldosterone induced leptin and Ob-R through GR but not MR: mifeprisotone (GR antagonist), but not eplerenone or spironolactone (MR antagonists), reduced both prednisolone- and aldosterone-induced leptin and Ob-R. GR silencing with shRNA confirmed these results.

(2)  GILZ was induced by prednisolone and aldosterone. Similarly to leptin, stimulations with GR or MR antagonists and GR silencing showed that both leptin and Ob-R inductions were GR-dependent: leptin and GILZ shared similar modulations. Moreover, CpdA and TGF-β, that did not induce GILZ in OA SF, did not induce leptin.

(3)  GILZ was involved in prednisolone- and aldosterone-induced leptin and Ob-R, with a significant dose-response decrease when GILZ was down-regulated by shRNA.

(4)  GILZ inhibition with shRNA did not modify the anti-inflammatory properties of prednisolone, with an unchanged endogenous or TNF-α-induced IL-6 reduction opposite to the control.

Conclusion:

(1)  Both mineralocorticoids and glucocorticoids induced leptin and Ob-R in OA SF, suggesting a deleterious involvement of both corticosteroids in the metabolic component of OA. Synovial tissue could represent a new target for mineralocorticoids.

(2)  Mechanistically, we propose a new role for GILZ in OA, with an involvement in corticosteroids-induced leptin and Ob-R. By contrast, GILZ did not seem significantly involved in the anti-inflammatory action of glucocorticoids in OA SF.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/leptin-production-by-osteoarthritis-synovial-fibroblasts-stimulation-by-glucocorticoids-and-mineralocorticoids-through-the-glucocorticoid-receptor-and-gilz-glucocorticoid-induced-leucine-zipper-pro/