Estrogen Receptor-Related Receptor α Regulation by Interleukin-1β in Prostaglandin E2- and cAMP-Dependent Pathways in Osteoarthritic Chondrocytes

Objective. We reported previously that the orphan nuclear receptor, estrogen receptor-related receptor alpha (ERR alpha), 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 ERR alpha is also dysregulated in patients with osteoarthritis (OA). Methods. ERR alpha 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. ERR alpha expression was lower in OA than in normal articular cartilage. Interleukin-1 beta (IL-1 beta) markedly up-regulated ERR alpha 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 E-2, cAMP (8-bromo-cAMP), and protein kinase A (PKA; KT5720). Treatment with the ERR alpha inverse agonist XCT790 decreased the expression of SOX9 and the up-regulation of ERR alpha by IL-1 beta, suggesting autoregulation of ERR alpha in the IL-1 beta pathway. Matrix metalloproteinase 13 (MMP-13) expression was also decreased by treatment with XCT790 plus IL-1 beta versus IL-1 beta 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-1 beta is ERR alpha-dependent. Conclusion. We report the first evidence that ERR alpha expression is regulated by IL-1 beta in COX-2-, cAMP-, and PKA-dependent pathways in OA chondrocytes. We confirmed that SOX9 is an ERR alpha target gene in human, as in rodent, chondrocytes and identified MMP-13 as a potential new target gene, which suggests that ERR alpha may both respond to the healing signal and contribute to extracellular degradation in OA cartilage.