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 ␣ (ERR␣), 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␣ is also dysregulated in patients with osteoarthritis (OA).Methods. ERR␣ 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 OAassociated factors and signaling pathway agonists and inhibitors.Results. ERR␣ expression was lower in OA than in normal articular cartilage. Interleukin-1␤ (IL-1␤) markedly up-regulated ERR␣ 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␣ inverse agonist XCT790 decreased the expression of SOX9 and the up-regulation of ERR␣ by IL-1␤, suggesting autoregulation of ERR␣ in the IL-1␤ pathway. Matrix metalloproteinase 13 (MMP-13) expression was also decreased by treatment with XCT790 plus IL-1␤ versus IL-1␤ 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␤ is ERR␣-dependent.Conclusion. We report the first evidence that ERR␣ expression is regulated by IL-1␤ in COX-2-, cAMP-, and PKA-dependent pathways in OA chondrocytes. We confirmed that SOX9 is an ERR␣ target gene in human, as in rodent, chondrocytes and identified MMP-13 as a potential new target gene, which suggests that ERR␣ may both respond to the healing signal and contribute to extracellular degradation in OA cartilage.Osteoarthritis (OA) is a chronic disease characterized by slowly progressive destruction of the articular cartilage, combined with changes in the synovium and subchondral bone (1). Various estimates suggest that more than 40% of 70-year-old people currently have the disease, ranking OA as the most common arthritic condition. The prevalence and the pain and disability associated with progression of the disease have led to intense interest in defining markers for OA as well as the mechanisms underlying the disease.The cellular component of cartilage is the chondrocyte, and adult articular chondrocytes, although considered quiescent in normal cartilage, can respond to mechanical injury and biologic stimuli such as cytokines and growth factors. Interleukin-1␤ (IL-1␤) is a wellknown proinflammatory cytokine that is implicated in

An energetic orphan in an endocrine tissue: A revised perspective of the function of estrogen receptor-related receptor alpha in bone and cartilage

“…1). Treatment with the ERRa inverse agonist XCT790, known to disrupt the interaction between ERRa and PGC1, decreased the expression of Sox9 in human OA chondrocytes, consistent with the view that ERRa and PGC1 together regulate Sox9 expression in chondrocytes supporting the hypothesis that they may function together in cartilage formation and maintenance (10) (Fig. 1).…”

“…(9,10) ERRa was also found to activate the Sox9 promoter and modulate Sox9 expression in a rat chondrogenic cell line (9) ( Fig. 1).…”

“…The data also implicate ERRa in cartilage maintenance in aging-related diseases such as rheumatoid arthritis and OA, where ERRa is dysregulated. (10,13) A role of ERRa in the Sox9 pathway is supported by the observation that one of its coactivators, PGC1a, is also expressed in chondrogenic sites where it coactivates Sox9 to regulate chondrogenesis (14) (Fig. 1).…”

“…1). Sox9 regulation by ERRa has been confirmed in patients with osteoarthritis (OA), a chronic disease characterized by slowly progressive destruction of the articular cartilage, (10,11) and in neonatal mouse calvarial explants overexpressing ERRa. (12) Experiments in which ERRa expression was downregulated in chondrogenic cells suggested that modulation of ERRa contributes to the maturation of proliferating chondrocytes to hypertrophy, most likely due to ERRa's direct or indirect regulation of Sox9.…”

“…In this article we do not review these in detail, but they include: (1) small heterodimer partner (SHP), which physically interacts with all three ERRs, repressing their activity (27)(28)(29) ; (2) hypoxia-inducible factor-a (HIF1a), which physically interacts with ERRa to stimulate HIF-induced transcription (30)(31)(32)(33) ; and (3) vascular endothelial growth factor (VEGF), which is a direct target gene of the ERRa/PGC1a complex and HIF1a in muscle and in breast cancer cells. (34,35) Several factors, including prostaglandin E1, BMP, and insulin-like growth factor 1, known to regulate ERRa or g expression and/or activity, also modulate VEGF production in bone cells, suggesting direct VEGF regulation by ERRa/g in OBs and OCs (10,25,38,39) ; (4) aryl hydrocarbon receptor (AhR), which has been reported to interact with ERa and ERRa (40)(41)(42)(43) ; (5) PPARa, which was reported to be directly regulated by ERRa in cardiac myocytes and skeletal muscles (44)(45)(46) ; and (6) Wnt11, which has been shown to be regulated in breast cancer cells by ERRa/b-catenin complex and in C3H10T1/2 cells through its interaction with PGC1a. (12,(47)(48)(49) Recently, we found osteoprotegerin (OPG) regulated in breast cancer cells impacting on bone metastases formation.…”