The Role of Aryl-Hydrocarbon Receptor (AhR) in Osteoclast Differentiation and Function

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays a crucial role in bone remodeling through altering the interplay between bone-forming osteoblasts and bone-resorbing osteoclasts. While effects of AhR signaling in osteoblasts are well understood, the role and mechanism of AhR signaling in regulating osteoclastogenesis is not widely understood. AhR, when binding with exogenous ligands (environmental pollutants such as polycylic aryl hydrocarbon (PAH), dioxins) or endogenous ligand indoxyl-sulfate (IS), has dual functions that are mediated by the nature of the binding ligand, binding time, and specific pathways of distinct ligands. In this review, AhR is discussed with a focus on (i) the role of AhR in osteoclast differentiation and function and (ii) the mechanisms of AhR signaling in inhibiting or promoting osteoclastogenesis. These findings facilitate an understanding of the role of AhR in the functional regulation of osteoclasts and in osteoclast-induced bone destructive conditions such as rheumatoid arthritis and cancer.

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A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth

Cancers ◽

10.3390/cancers11050589 ◽

2019 ◽

Vol 11 (5) ◽

pp. 589 ◽

Cited By ~ 4

Author(s):

Christoph F. A. Vogel ◽

Yasuhiro Ishihara ◽

Claire E. Campbell ◽

Sarah Y. Kado ◽

Aimy Nguyen-Chi ◽

...

Keyword(s):

Tumor Growth ◽

Aryl Hydrocarbon Receptor ◽

Inflammatory Responses ◽

Environmental Pollutants ◽

Protective Role ◽

Potential Therapeutic Target ◽

Embryonic Fibroblasts ◽

Aryl Hydrocarbon ◽

Enhancer Binding Protein

The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR’s functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.

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Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor

International Journal of Molecular Sciences ◽

10.3390/ijms21103486 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3486 ◽

Cited By ~ 3

Author(s):

Wen-Chih Liu ◽

Jia-Fwu Shyu ◽

Paik Seong Lim ◽

Te-Chao Fang ◽

Chien-Lin Lu ◽

...

Keyword(s):

Transcription Factor ◽

Aryl Hydrocarbon Receptor ◽

Critical Role ◽

Osteoclast Differentiation ◽

Indoxyl Sulfate ◽

Raw 264.7 Cells ◽

High Dose ◽

Activated T Cells ◽

Aryl Hydrocarbon

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.

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The Aryl Hydrocarbon Receptor in Asthma: Friend or Foe?

International Journal of Molecular Sciences ◽

10.3390/ijms21228797 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8797

Author(s):

Odile Poulain-Godefroy ◽

Mélodie Bouté ◽

Julie Carrard ◽

Daniel Alvarez-Simon ◽

Anne Tsicopoulos ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Asthmatic Patients ◽

Aryl Hydrocarbon ◽

Important Player ◽

Polycyclic Aromatic ◽

Exogenous Ligands ◽

Anti Inflammatory ◽

Antigen Presenting ◽

Two Sides

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has emerged as an important player in asthma control. AhR is responsive to environmental molecules and endogenous or dietary metabolites and regulates innate and adaptive immune responses. Binding of this receptor by different ligands has led to seemingly opposite responses in different asthma models. In this review, we present two sides of the same coin, with the beneficial and deleterious roles of AhR evaluated using known endogenous or exogenous ligands, deficient mice or antagonists. On one hand, AhR has an anti-inflammatory role since its activation in dendritic cells blocks the generation of pro-inflammatory T cells or shifts macrophages toward an anti-inflammatory M2 phenotype. On the other hand, AhR activation by particle-associated polycyclic aromatic hydrocarbons from the environment is pro-inflammatory, inducing mucus hypersecretion, airway remodelling, dysregulation of antigen presenting cells and exacerbates asthma features. Data concerning the role of AhR in cells from asthmatic patients are also reviewed, since AhR could represent a potential target for therapeutic immunomodulation.

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Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction

Reproduction ◽

10.1530/rep.1.00294 ◽

2005 ◽

Vol 129 (4) ◽

pp. 379-389 ◽

Cited By ~ 124

Author(s):

P Pocar ◽

B Fischer ◽

T Klonisch ◽

S Hombach-Klonisch

Keyword(s):

Transcription Factor ◽

Aryl Hydrocarbon Receptor ◽

Reproductive Tract ◽

Wide Spectrum ◽

Environmental Pollutants ◽

Large Body ◽

Female Reproductive Tract ◽

Female Reproduction ◽

Aryl Hydrocarbon

The dioxin/aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor responsive to both natural and man-made environmental compounds. AhR and its nuclear partner ARNT are expressed in the female reproductive tract in a variety of species and several indications suggest that the AhR might play a pivotal role in the physiology of reproduction. Furthermore, it appears to be the mediator of most, if not all, the adverse effects on reproduction of a group of highly potent environmental pollutants collectively called aryl hydrocarbons (AHs), including the highly toxic compound 2,3,7,8-tetrachlor-odibenzo-p-dioxin (TCDD). Although a large body of recent literature has implicated AhR in multiple signal transduction pathways, the mechanisms of action resulting in a wide spectrum of effects on female reproduction are largely unknown. Here we summarize the major types of molecular cross-talks that have been identified for the AhR and linked cell signaling pathways and that are relevant for the understanding of the role of this transcription factor in female reproduction.

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Inhibition of Human Osteoclast Differentiation by Kynurenine through the Aryl-Hydrocarbon Receptor Pathway

Cells ◽

10.3390/cells10123498 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3498

Author(s):

So-Yeon Kim ◽

Younseo Oh ◽

Sungsin Jo ◽

Jong-Dae Ji ◽

Tae-Hwan Kim

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Inflammatory Diseases ◽

Early Stage ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Osteoclast Formation ◽

Aryl Hydrocarbon ◽

Human Osteoclast ◽

And Function ◽

Human Osteoclasts

Aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor and regulates differentiation and function of various immune cells such as dendritic cells, Th17, and regulatory T cells. In recent studies, it was reported that AhR is involved in bone remodeling through regulating both osteoblasts and osteoclasts. However, the roles and mechanisms of AhR activation in human osteoclasts remain unknown. Here we show that AhR is involved in human osteoclast differentiation. We found that AhR expressed highly in the early stage of osteoclastogenesis and decreased in mature osteoclasts. Kynurenine (Kyn), formylindolo[3,4-b] carbazole (FICZ), and benzopyrene (BaP), which are AhR agonists, inhibited osteoclast formation and Kyn suppressed osteoclast differentiation at an early stage. Furthermore, blockade of AhR signaling through CH223191, an AhR antagonist, and knockdown of AhR expression reversed Kyn-induced inhibition of osteoclast differentiation. Overall, our study is the first report that AhR negatively regulates human osteoclast differentiation and suggests that AhR could be good therapeutic molecule to prevent bone destruction in chronic inflammatory diseases such as rheumatoid arthritis (RA).

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