WIN 64338 hydrochloride ERR is constitutively active in the
ERRγ is constitutively active in the absence of endogenous ligand. However, several synthetic ligands that can repress or induce ERRγ function by disrupting ERRγ-coactivator interactions have been reported to date. The estrogen receptor modulators diethylstilbestrol (DES) and 4-hydroxytamoxifen (4-OHT) act as inverse agonists to suppress the intrinsic transcriptional activity of ERRγ. GSK5182, a 4-OHT analog, is thought to show higher inverse agonist specificity for ERRγ than 4-OHT, because it contributes to non-covalent interactions with Y326 and N346 at the active site of the ERRγ LBD. In addition, GSK4716 and DY131, phenolic acyl hydrazines, increase the basal activity of ERRβ and ERRγ., Bisphenol A, an endocrine disruptor, binds to human ERRγ with high affinity and acts as an antagonist of the inverse agonist activity of 4-OHT on ERRγ. As these synthetic ligands affect various metabolic functions of ERRγ in vitro and in vivo, they are useful tools for studying the metabolic functions of ERRγ and may also have therapeutic potential in metabolic diseases caused by ERRγ dysregulation.
Roles of ERRγ in liver metabolism and disease
Conclusions Recent progress in our understanding of the ligand-independent activity of ERRγ suggests that this receptor is an inducible transcription factor that functions as a downstream mediator of endocrine and metabolic signals, such as glucagon, insulin, and endocannabinoids (Fig. 2). Moreover, the transcriptional activity of ERRγ is tightly regulated by co-regulators and post-translational modifications. As a result, ERRγ directly or indirectly regulates the expression of key metabolic WIN 64338 hydrochloride and major hormones in the liver, leading to diverse metabolic outcomes. Considering the pleiotropic roles of ERRγ in different physiological and pathophysiological conditions in the liver, targeting ERRγ might provide a therapeutic approach for ERRγ-mediated metabolic diseases (Table 1). Future studies aimed at characterizing its endogenous ligand would further bolster our understanding of its function, provide us with necessary experimental tools, and facilitate the development of additional therapeutic strategies for the treatment of metabolic disorders related to the activity of ERRγ.
Conflict of interest
The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERRα, ERRβ and ERRγ, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. However, the functions of ERRs in regulating joint cartilage homeostasis and/or OA pathogenesis have not yet been studied. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Human OA cartilage was sourced from individuals undergoing arthroplasty. C57BL/6J mice were used for the experimental OA studies. mice (B6.129P2-/Mmnc) were purchased from the Mutant Mouse Regional Resource Center (MMRRC). Tg mice were generated using the promoter and enhancer. Human OA cartilage was frozen, sectioned at a thickness of 5 μm, and fixed in paraformaldehyde. Sulfate proteoglycans were detected by alcian blue staining, and cartilage destruction in mice was examined using safranin-O staining. Femoral condyles and tibial plateaus were obtained from mice, and chondrocytes were isolated from cartilage tissue by digestion with 0.2% collagenase. Among the ERR family members, ERRγ was specifically upregulated in cartilage from human OA patients and various mouse models of OA. Gain-of-function (adenovirus-mediated overexpression in joint tissues or Tg mice) and loss-of-function ( mice or shRNA-mediated knockdown) approaches clearly indicated that ERRγ acts as a novel catabolic regulator of OA pathogenesis, at least in part, by the upregulating matrix-degrading enzymes, MMP3 and MMP13, in articular chondrocytes.