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The retinoic acid receptor-related orphan receptor alpha (RORα) is a member of the nuclear hormone receptor superfamily. Several studies show that estradiol is related to RORα expression. However, the link between estradiol and RORα in osteoblast differentiation remains unknown. Here, we showed that estradiol induces RORα expression in C3H10T1/2 and MC3T3-E1 cells. RORα overexpression increased the expression of osteogenic genes including bone morphogenetic protein 2 (BMP2), distal-less homeobox 5, inhibitor of DNA binding, runt-related transcription factor 2 (Runx2), and osteocalcin. In addition, RORα increased phosphorylation of smad1/5/9. Furthermore, RORα knockdown suppressed estradiol-induced BMP2 and Runx2 protein level. Also, we confirmed that estradiol-induced ALP staining and matrix mineralization was attenuated in RORα knockdown. Summarily, these results suggest that estradiol-induced RORα promotes osteoblast differentiation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Receptor interacting protein 2 (RIP2) plays a role in sensing intracellular pathogens, but its function in T cells is unclear. We show that RIP2 deficiency in CD4 + T cells resulted in chronic and severe interleukin-17A-mediated inflammation during Chlamydia pneumoniae lung infection, increased T helper 17 (Th17) cell formation in lungs of infected mice, accelerated atherosclerosis, and more severe experimental autoimmune encephalomyelitis. While RIP2 deficiency resulted in reduced conventional Th17 cell differentiation, it led to significantly enhanced differentiation of pathogenic (p)Th17 cells, which was dependent on RORα transcription factor and interleukin-1 but independent of nucleotide oligomerization domain (NOD) 1 and 2. Overexpression of RIP2 resulted in suppression of pTh17 cell differentiation, an effect mediated by its CARD domain, and phenocopied by a cell-permeable RIP2 CARD peptide. Our data suggest that RIP2 has a T cell-intrinsic role in determining the balance between homeostatic and pathogenic Th17 cell responses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Low O 2 pressures present in the microenvironment of epidermis control keratinocyte differentiation and epidermal barrier function through hypoxia inducible factors (HIFs) dependent gene expression. This study focuses on investigating relations of the retinoic acid receptor-related orphan receptor alpha (RORα) to HIF-1α in keratinocytes under hypoxic conditions. The expression level of RORα is significantly elevated under hypoxia in both human and murine keratinocytes. Gene silencing of RORA attenuates hypoxia-stimulated expression of genes related to late differentiation and epidermal barrier function, and leads to an enhanced apoptotic response. While the hypoxic induction of RORα is dependent on HIF-1α, RORα is in turn critical for nuclear accumulation of HIF-1α and activation of HIF transcriptional activity. These results collectively suggest that RORα functions as an important mediator of HIF-1α activities in regulating keratinocyte differentiation/survival and epidermal barrier function during the oxygen sensing stage., (© 2017 Wiley Periodicals, Inc.)

The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Macrophages are able to polarize to pro-inflammatory M1 or anti-inflammatory M2 states with distinct phenotypes and physiological functions. RORα is a member of the nuclear receptor super family and plays important roles in lipid, glucose metabolism, as well as the inflammatory response. In this study, we examined the potential function of RORα in the regulation of macrophage polarization. Treatment of RAW264.7 macrophages with RORα agonist cholesterol sulfate (CH-S) and overexpression of RORα increased M2 macrophage markers expressions (Arg1, Ym1 and Fizz1) both on mRNA and protein levels. Conversely, selective antagonism (SR1001) abrogated the induction of M2 macrophage markers which induced by CH-S. In addition, CH-S induced phosphorylation of Adenosine monophosphate (AMP)-activated protein kinase α (AMPKα), which was accompanied by the activation of acetyl-CoA carboxylase 1 (ACC). However, SR1001 abolished the activation of AMPKα and ACC induced by CH-S. Meanwhile, inactivation of AMPKα by its inhibitor Compound C (CompC) abrogated the mRNA and protein levels of CH-S-induced M2 macrophage markers expressions. Together these findings reveal that RORα regulates macrophage M2 polarization via activation of AMPKα, which may provide a novel beneficial effect of RORα against inflammation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The population of T lymphocytes producing IL‐17 (Th17) plays a dual role during pregnancy and its activity is tightly controlled during this period. One of the factors involved in this process may be the pineal hormone melatonin, which can effectively regulate this T cell population. Here we have shown that exogenous melatonin in pharmacological concentrations is able to enhance the differentiation of Th17 cells of pregnant women in vitro. The stimulatory effects of melatonin were limited to in the first trimester of pregnancy and were apparently mediated by both membrane and nuclear melatonin receptors. Since exogenous melatonin is currently considered as a promising drug in solving various problems associated with reproduction, it is necessary to take into account its immunoregulatory effects. [ABSTRACT FROM AUTHOR]

BACKGROUND: The orphan nuclear receptors Rev-erbα and Rorα play important roles in lipid metabolism and glucose metabolism. But it is unclear whether they are involved in bone metabolism. OBJECTIVE: To observe the expression of Rev-erbα and Rorα during the osteoblastogenesis process of bone marrow mesenchymal stem cells (BMSCs). METHODS: BMSCs were isolated and purified from C57BL/6 mice by the whole bone marrow adherence method followed by morphology observations and then BMSCs were induced to differentiate into osteoblasts and adipocytes. We detected their differentiation abilities using oil red O staining and alizarin red staining, respectively. Real-time PCR and western blot assay were conducted to detect the mRNA and protein levels of Rev-erbα and Rorα in BMSCs cultured in the osteogenic medium for 0, 7, 14 days. RESULTS AND CONCLUSION: BMSCs from C57BL/6 mice were mainly spindle-shaped and exhibited the swirl-like pattern of growth. Following induction, oil red O staining and alizarin red staining produced a positive reaction in these cells. Rev-erbα expression at both gene and protein levels decreased at 0, 7, 14 days after osteogenic induction, while Rorα expression increased at both gene and protein levels. These findings indicate that Rev-erbα and Rorα may participate in the osteoblastogenesis of BMSCs. [ABSTRACT FROM AUTHOR]

Abstract: Purkinje cells (PCs) provide the primary output from the cerebellar cortex, which controls movement and posture, and loss of PCs causes severe cerebellar dysfunction. The mechanisms underlying cell fate determination and early differentiation of PC remain largely unknown. Here we show that the c-Ski family member and transcriptional regulator Corl2 is required for correct differentiation of PCs. In Corl2 knock-out embryos, initial PC specification appeared largely normal, but in a subset of presumptive PCs generated near the ventral border of the PC domain, cell fate choice was compromised and cells showed a mixed identity expressing the interneuron marker Pax2 as well. Additionally, selection and maintenance of the transmitter phenotype was compromised in most developing PCs in the mutants. During later differentiation steps, induction of PC marker genes was significantly suppressed, suggesting that maturation was delayed in the absence of Corl2. Consistently, defects in migration, cell polarization and dendrite formation were observed in mutant PCs, although their axonal trajectories appeared normal. These phenotypes closely resembled those of mutants for Rora, an essential regulator of PC differentiation. However, Rora expression was not significantly changed in the Corl2 mutants, indicating that Corl2 does not simply act upstream of Rora to promote PC differentiation. ChIP experiments revealed that Corl2 bound to the promoter regions of several PC-selective genes, which are also known to be direct downstream targets of RORα. Altogether, our results identified a novel regulatory program of PC differentiation involving Corl2, which might cooperate with the RORα pathway. [Copyright &y& Elsevier]

. T helper cells17 (Th17) have accurate but inconclusive roles in the pathogenesis of acute-on-chronic hepatitis B liver failure (ACHBLF). Retinoic acid-related orphan receptor γ t(RORγt) and RORα are two lineage-specific nuclear receptors directly mediating Th17 differentiation. This study was aimed to evaluate the gene expression of RORα and RORγt and their potential role in ACHBLF. Forty patients with liver failure, 30 with chronic hepatitis B (CHB) and 20 healthy controls were studied. The mRNA levels of RORα and RORγt in peripheral mononuclear cells were determined by quantitative real-time polymerase chain reaction. The frequency of peripheral Th17 cells was determined using flow cytometry. The serum levels of interleukin-6(IL-6), transforming growth factor -β (TGF-β), interleukin-17(IL-17), interleukin-23(IL-23) and interferon-γ (IFN-γ) were measured by enzyme-linked immunosorbent assay. The frequency of peripheral Th17 cells in patients with liver failure was significantly increased compared to patients with CHB and controls. The peripheral mRNA levels of RORα and RORγt in hepatitis B-associated acute-on-chronic liver failure were significantly higher than in patients with CHB and controls as were the serum levels of IL-6 and TGF-β. The serum level of IFN-γ in patients with acute-on-chronic liver failure from HBV was significantly higher than patients with CHB but lower than controls. In patients with acute-on-chronic liver failure associated with HBV, RORγt, IL-6 and IL-23 were positively correlated with the frequency of Th17 cells, while RORα, TGF-β and IFN-γ had no correlation with the latter. The mRNA level of RORγt was positively correlated with model of end-stage liver disease (MELD) score, but there was no correlation of RORα and MELD score. RORγt plays an important role in the pathogenesis of acute-on-chronic HBV-associated liver failure and might be considered to be a candidate factor consistent with the severity of disease. [ABSTRACT FROM AUTHOR]

Abstract: Here we show that gene expression of the nuclear receptor RORα is induced during adipogenesis, with RORα4 being the most abundantly expressed isoform in human and murine adipose tissue. Over-expression of RORα4 in 3T3-L1 cells impairs adipogenesis as shown by the decreased expression of adipogenic markers and lipid accumulation, accompanied by decreased free fatty acid and glucose uptake. By contrast, mouse embryonic fibroblasts from staggerer mice, which carry a mutation in the RORα gene, differentiate more efficiently into mature adipocytes compared to wild-type cells, a phenotype which is reversed by ectopic RORα4 restoration. [Copyright &y& Elsevier]

Dendritic differentiation involves both regressive and growth events. The mechanisms controlling the regressive events are poorly understood. This study is aimed at determining the role of the nuclear receptor retinoid-related orphan receptor α (RORα) in Purkinje cell (PC) dendritic differentiation in organotypic cultures. As observed in vivo, in these cultures, fusiform PCs with embryonic bipolar shape undergo regression before the outgrowth of the ultimate dendritic tree. We show that lentiviral-mediated hRORα1 overexpression in fusiform PCs leads to a cell-autonomous accelerated progression of dendritic differentiation. In addition, RORαis necessary for the PC regressive events: whereas staggerer RORα-deficient PCs remain in the embryonic fusiform stage, replacement of hRORα1 restores normal dendritogenesis. These results demonstrate that RORαexpression in fusiform PCs is crucial for the dendritic regression and progression of the following step of extension of dendritic processes. However, it does not seem to participate to the last stage of dendritic growth. This study identifies RORα as a nuclear receptor crucial for the control of dendritic remodeling during development. [ABSTRACT FROM AUTHOR]