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Estrogen receptor-related receptor α regulation by interleukin-1β in prostaglandin E2- and cAMP-dependent pathways in osteoarthritic chondrocytes

Abstract : Objective: We reported previously that the orphan nuclear receptor, estrogen receptor–related receptor α (ERRα), is expressed in articular chondrocytes and is dysregulated in a mouse model of inflammatory arthritis. The aim of this study, therefore, was to determine whether ERRα is also dysregulated in patients with osteoarthritis (OA). Methods: ERRα messenger RNA (mRNA) and protein were quantified in normal and OA cartilage samples and in OA chondrocytes in vitro, with and without short-term treatment with a variety of OA-associated factors and signaling pathway agonists and inhibitors. Results: ERRα expression was lower in OA than in normal articular cartilage. Interleukin-1β (IL-1β) markedly up-regulated ERRα expression in OA chondrocytes in vitro, and agonist or inhibitor treatment indicated that the up-regulation was dependent on cyclooxygenase 2 (COX-2; NS398), prostaglandin E2, cAMP (8-bromo-cAMP), and protein kinase A (PKA; KT5720). Treatment with the ERRα inverse agonist XCT790 decreased the expression of SOX9 and the up-regulation of ERRα by IL-1β, suggesting autoregulation of ERRα in the IL-1β pathway. Matrix metalloproteinase 13 (MMP-13) expression was also decreased by treatment with XCT790 plus IL-1β versus IL-1β alone, and the down-regulation of MMP-13 mRNA and protein observed with XCT790 alone suggests that the up-regulation of MMP-13 by IL-1β is ERRα-dependent. Conclusion: We report the first evidence that ERRα expression is regulated by IL-1β in COX-2–, cAMP-, and PKA-dependent pathways in OA chondrocytes. We confirmed that SOX9 is an ERRα target gene in human, as in rodent, chondrocytes and identified MMP-13 as a potential new target gene, which suggests that ERRα may both respond to the healing signal and contribute to extracellular degradation in OA cartilage.
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https://hal.univ-lorraine.fr/hal-01705064
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Submitted on : Friday, February 9, 2018 - 8:59:56 PM
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Edith Bonnelye, Pascal Reboul, Nicolas Duval, Marco Cardelli, Jane Aubin. Estrogen receptor-related receptor α regulation by interleukin-1β in prostaglandin E2- and cAMP-dependent pathways in osteoarthritic chondrocytes. Arthritis and Rheumatism, Wiley, 2011, 63 (8), pp.2374-2384. ⟨10.1002/art.30398⟩. ⟨hal-01705064⟩

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