The role of aryl hydrocarbon receptor in bone remodeling

Yu, Hao; Jiang, Lili; Wan, Bo; Zhang, Wei; Yao, Liqiong; Che, Tuanjie; Gan, Chao; Su, Na; He, Jiaqing; Huang, Jintian; Chen, Yinran; Zhang, Yiheng

doi:10.1016/j.pbiomolbio.2017.12.005

Cited by 28 publications

(20 citation statements)

References 91 publications

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“…Considering that the AhR antagonist 2’,4’,6-trimethoxyflavone or inhibition of kynurenine synthesis decreased stroke-associated damage, it is conceivable that the AhR plays a role in this condition [ 82 ]. Several studies demonstrate the role of the AhR and its ligands (e.g., TCDD and benzo[a]pyrene) on bone, although there are some response-specific differences reported in rodent models [ 83 , 84 , 85 , 86 , 87 ]. In AhR null mice, there is an increase in bone volume fraction and decreased bone turnover and effects of ligands are variable and age-dependent.…”

Section: Ahr Expression/function In Pathophysiologymentioning

confidence: 99%

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Safe

Jin

Park

et al. 2020

IJMS

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The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.

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Section: Ahr Expression/function In Pathophysiologymentioning

confidence: 99%

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Safe

Jin

Park

et al. 2020

IJMS

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“…To date, the role of environmental contaminants in the development of metabolic bone disorders has not been thoroughly investigated. However, several persistent environmental contaminants such as 2,3,7,8-tetrachlordibenzo- p -dioxin (TCDD) are potent activators of the aryl hydrocarbon receptor (AhR), which is known to regulate bone development, mineralization, and remodeling (Yu et al ., 2017). The AhR is a basic helix-loop-helix Per-Arnt-Sim (PAS) transcription factor which elicits gene expression changes in a species-, sex-, age-, tissue-, and cell-specific manner (Denison and Nagy, 2003).…”

Section: Introductionmentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice

Fader

Nault

Raehtz

et al. 2018

Toxicology and Applied Pharmacology

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) agonists have been shown to regulate bone development and remodeling in a species-, ligand-, and age-specific manner, however the underlying mechanisms remain poorly understood. In this study, we characterized the effect of 0.01-30 μg/kg TCDD on the femoral morphology of male and female juvenile mice orally gavaged every 4 days for 28 days and used RNA-Seq to investigate gene expression changes associated with the resultant phenotype. Micro-computed tomography revealed that TCDD dose-dependently increased trabecular bone volume fraction (BVF) 2.9- and 3.3-fold in male and female femurs, respectively. Decreased serum tartrate-resistant acid phosphatase (TRAP) levels, combined with a reduced osteoclast surface to bone surface ratio and repression of femoral proteases (cathepsin K, matrix metallopeptidase 13), suggests that TCDD impaired bone resorption. Increased osteoblast counts at the trabecular bone surface were consistent with a reciprocal reduction in the number of bone marrow adipocytes, suggesting AhR activation may direct mesenchymal stem cell differentiation towards osteoblasts rather than adipocytes. Notably, femoral expression of transmembrane glycoprotein NMB (Gpnmb; osteoactivin), a positive regulator of osteoblast differentiation and mineralization, was dose-dependently induced up to 18.8-fold by TCDD. Moreover, increased serum levels of 1,25-dihydroxyvitamin D were in accordance with the renal induction of 1α-hydroxylase Cyp27b1 and may contribute to impaired bone resorption. Collectively, the data suggest AhR activation tipped the bone remodeling balance towards bone formation, resulting in increased bone mass with reduced marrow adiposity.

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“…Environment‐related pathophysiological contributors include bioaccumulation of organic pollutants in near‐shore marine food webs (Sonne et al, 2004). Some compounds produce endocrine‐disrupting effects on vitamin D and thyroid hormones, resulting in bone abnormalities (Hodgson et al, 2008; Yu et al, 2018). Endocrine‐disrupting chemicals (EDCs) are “exogenous chemical(s), or mixtures of chemicals, that interfere with any aspect of hormone action” and can exert effects at “extremely low concentrations” (Gore et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Lower bone mineral density has been associated with low‐level OCs exposure in polar bears (Sonne et al, 2004) and Inuit humans (Hodgson et al, 2008). A possible pathophysiological mechanism involves induction of the aryl hydrocarbon receptor, a transcription factor that inhibits osteoblast formation and differentiation (Yu et al, 2018). Another possible mechanism is OCs alteration of vitamin A‐related enzyme activity, leading to secondary deficiency (Simms & Ross, 2000).…”

Section: Discussionmentioning

confidence: 99%

Skeletal remains of five blue foxes (Vulpes lagopus) from St. Paul Island, Pribilof Islands, Alaska: A view of differential diagnosis

Lawler

Tangredi

Etnier

2021

Intl J of Osteoarchaeology

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We evaluated skeletal remains of five blue arctic foxes from St. Paul Island, Pribilof Islands, Alaska. All five had been found dead. Cleared skeletal remains were examined visually and by magnification or backlighting where necessary. Pathological features were described and photographed. Results suggested that more than one disorder may have occurred in these foxes, with primary observations being demineralizing and/or proliferation. Most prominently affected were the skull, maxillae, mandibles, pelvis, long bones, and major diarthrodial joints. It was critically important to recognize certain other pathological features that can be observed on many or most fox skeletal remains but are unlikely to relate to conditions that demineralize bone or cause overt bone loss, multifocal loss of joint architecture, or severe multifocal periarticular boney proliferation. The differential diagnosis of canid skeletal demineralizing includes primary and secondary (nutritional or renal) hyperparathyroidism. Boney proliferation has a wider differential spectrum that can include hypervitaminosis A, osteomyelitis, abnormalities related to inbreeding, and environmental toxicosis. In our view, given the lack of soft tissue for histological evaluation and biochemical analysis, a well‐considered differential diagnosis is an appropriate scientific point of conclusion. In the many similar circumstances that would require additional studies for valid definitive diagnosis during life, investigators should review relevant literature and consider the value of well‐structured differential diagnosis, as contrasted with more speculative definitive diagnoses.

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The role of aryl hydrocarbon receptor in bone remodeling

Cited by 28 publications

References 91 publications

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice

Skeletal remains of five blue foxes (Vulpes lagopus) from St. Paul Island, Pribilof Islands, Alaska: A view of differential diagnosis

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