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Review
. 2022 Aug 22;69(3):R109-R124.
doi: 10.1530/JME-22-0076. Print 2022 Oct 1.

Aryl hydrocarbon receptor (AhR)-mediated signaling as a critical regulator of skeletal cell biology

Dima W Alhamad  1 , Husam Bensreti  1 , Jennifer Dorn  1 , William D Hill  2   3 , Mark W Hamrick  1 , Meghan E McGee-Lawrence  1   4
Affiliations
Review

Aryl hydrocarbon receptor (AhR)-mediated signaling as a critical regulator of skeletal cell biology

Dima W Alhamad et al. J Mol Endocrinol. .

Abstract

The aryl hydrocarbon receptor (AhR) has been implicated in regulating skeletal progenitor cells and the activity of bone-forming osteoblasts and bone-resorbing osteoclasts, thereby impacting bone mass and the risk of skeletal fractures. The AhR also plays an important role in the immune system within the skeletal niche and in the differentiation of mesenchymal stem cells into other cell lineages including chondrocytes and adipocytes. This transcription factor responds to environmental pollutants which can act as AhR ligands, initiating or interfering with various signaling cascades to mediate downstream effects, and also responds to endogenous ligands including tryptophan metabolites. This review comprehensively describes the reported roles of the AhR in skeletal cell biology, focusing on mesenchymal stem cells, osteoblasts, and osteoclasts, and discusses how AhR exhibits sexually dimorphic effects in bone. The molecular mechanisms mediating AhR's downstream effects are highlighted to emphasize the potential importance of targeting this signaling cascade in skeletal disorders.

Keywords: bone; nuclear receptors; osteoblast; osteoclast; skeletal.

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Conflict of interest statement

Declaration of Interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported in this review.

Figures

Figure 1:
Figure 1:. Canonical and non-canonical AhR signaling pathways.
Upon binding to an agonist, such as kynurenine (KYN), AhR leaves its chaperone complex and translocates to the nucleus. In the canonical pathway, AhR interacts with ARNT and binds the xenobiotic response element (XRE) nucleotide sequence to drive the expression of target genes including CYP1A1 and CYP1B1. The non-canonical pathway, in contrast, involves the interaction of AhR and KLF6 binding to a non-consensus XRE (NC-XRE) nucleotide sequence to drive expression of target genes including PAI-1 and p21cip1. Figure created with BioRender.com.
Figure 2:
Figure 2:. Reported effects of AhR signaling in bone cells.
AhR has been reported to exhibit a diverse array of effects in cells of the MSC and HSC lineages, with many effects occurring in a ligand- and cell type-dependent fashion. Figure created with BioRender.com.
See this image and copyright information in PMC

References

    1. Abney KK and Galipeau J (2021). "Aryl hydrocarbon receptor in mesenchymal stromal cells: new frontiers in AhR biology." FEBS J 288(13): 3962–3972. - PubMed
    1. Al-Bashaireh AM, Haddad LG, Weaver M, Chengguo X, Kelly DL and Yoon S (2018). "The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms." J Osteoporos 2018: 1206235. - PMC - PubMed
    1. Amenya HZ, Tohyama C and Ohsako S (2016). "Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver." Sci Rep 6: 34989. - PMC - PubMed
    1. An L, Shi Q, Fan M, Huang G, Zhu M, Zhang M, Liu Y and Weng Y (2020). "Benzo[a]pyrene injures BMP2-induced osteogenic differentiation of mesenchymal stem cells through AhR reducing BMPRII." Ecotoxicol Environ Saf 203: 110930. - PubMed
    1. Arinze NV, Yin W, Lotfollahzadeh S, Napoleon MA, Richards S, Walker JA, Belghasem M, Ravid JD, Hassan Kamel M, Whelan SA, Lee N, Siracuse JJ, Anderson S, Farber A, Sherr D, Francis J, Hamburg NM, Rahimi N and Chitalia VC (2022). "Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease." J Clin Invest 132(1). - PMC - PubMed

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