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Review
. 2024 May 15:17:11786469241246674.
doi: 10.1177/11786469241246674. eCollection 2024.

The Role of Aryl Hydrocarbon Receptor in Bone Biology

Sagar Vyavahare  1 , Pankaj Ahluwalia  2 , Sonu Kumar Gupta  1 , Ravindra Kolhe  2 , William D Hill  3 , Mark Hamrick  4   5 , Carlos M Isales  1   5 , Sadanand Fulzele  1   4   5
Affiliations
Review

The Role of Aryl Hydrocarbon Receptor in Bone Biology

Sagar Vyavahare et al. Int J Tryptophan Res. .

Abstract

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is crucial in maintaining the skeletal system. Our study focuses on encapsulating the role of AhR in bone biology and identifying novel signaling pathways in musculoskeletal pathologies using the GEO dataset. The GEO2R analysis identified 8 genes (CYP1C1, SULT6B1, CYB5A, EDN1, CXCR4B, CTGFA, TIPARP, and CXXC5A) involved in the AhR pathway, which play a pivotal role in bone remodeling. The AhR knockout in hematopoietic stem cells showed alteration in several novel bone-related transcriptomes (eg, Defb14, ZNF 51, and Chrm5). Gene Ontology Enrichment Analysis demonstrated 54 different biological processes associated with bone homeostasis. Mainly, these processes include bone morphogenesis, bone development, bone trabeculae formation, bone resorption, bone maturation, bone mineralization, and bone marrow development. Employing Functional Annotation and Clustering through DAVID, we further uncovered the involvement of the xenobiotic metabolic process, p450 pathway, oxidation-reduction, and nitric oxide biosynthesis process in the AhR signaling pathway. The conflicting evidence of current research of AhR signaling on bone (positive and negative effects) homeostasis may be due to variations in ligand binding affinity, binding sites, half-life, chemical structure, and other unknown factors. In summary, our study provides a comprehensive understanding of the underlying mechanisms of the AhR pathway in bone biology.

Keywords: Aryl hydrocarbon receptor; osteoblasts; osteoclasts.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Schematic representation of AhR canonical signaling pathway. AhR forms a complex comprising of AhR, 2 heat shock protein 90, and X-associated protein 2 (XAP-2) in the cytosol. After activation through ligands, AhR is translocated from the cytoplasm to the nucleus, where it dissociates itself from the complex. Further, the ligand-AhR complex combines with the AhR nuclear translocator (ARNT) and binds to a specific DNA promoter sequence called a xenobiotic responsive element (XRE), which leads to the activation of genes (CYP1A1, CYP1A2, CYP1B1, IDO).
Figure 2.
Figure 2.
Schematic representation of AhR-NF-κB signaling pathway. AhR binds to different NF-κB subunits, and the AhR-NF-κB signaling pathway is activated. RelB, an NF-κB component, interacts with AhR to coordinate the AhR pathway. AhR ligands, including 3 -MC, BaP, and β-NF, bind to NF-κB membrane receptors and further restrict the development of osteoclasts by direct effect on the NF-κB pathway.
Figure 3.
Figure 3.
Schematic representation of AhR-Wnt signaling pathway. The Wnt signaling pathway is activated when the AhR ligand TCDD binds to the aryl hydrocarbon receptor (AhR) and increases the expression of R Spondin 1 (Rspo1). Wnt signaling activation happens in an AhR-dependent way and directly affects osteoblast differentiation and proliferation. Lipoprotein receptor protein 5 (LRP5) and lipoprotein receptor protein 6 (LRP6) ligands are recognized by Wnt proteins. After binding, it causes β-catenin to be stabilized and enriched in the cytoplasm. Additionally, this activated β-catenin moves into the nucleus, where it interacts with the Runx2 transcription factor for osteoblasts to promote bone production.
Figure 4.
Figure 4.
Schematic representation of AhR-MAPK signaling pathway. AhR binds to its ligand (TCDD) to activate the MAPK pathway. When a ligand binds to the inactivated AhR, which is present in the cytoplasm as part of a complex with HSP90 dimer, XAP-2, p23, and SRC (steroid receptor coactivator) protein kinase, the complex dissociates, and the inactivated AhR is transported into the nucleus by ARNT, causing conformational changes. Additionally, the complex’s dissociated components, like SRC, further stimulate the MAPK pathway through Ras-Raf signaling. Once SRC is activated, it triggers cascade events and starts ERK, p-38, and C-JUN-N signaling, which causes Runx2 to be phosphorylated and activated. Runx2 is thought to be the primary transcription factor to produce bone matrix, osteoblast differentiation, and proliferation.
Figure 5.
Figure 5.
AhR activation regulates bone remodeling genes in Zebrafish. GEO2R data analysis showing 8 bone homeostasis-related genes (CYP1C1, SULT6B1, CYB5A, EDN1, CXCR4B, CTGFA, TIPARP, and CXXC5A) differentially regulated after activation of AhR signaling in jaw of Zebrafish. The data were retrieved from the GEO dataset uploaded by Xiong et al (GEO accession GSE11893); significance was determined by GEO2R adjusted *P-value < .05. **P-value < .001 (n = 3/group).
Figure 6.
Figure 6.
Identification of novel bone-related genes involved in AhR signaling with age: GEO2R study (Young AhR KO vs Young Floxed AhR) showing elevated levels of (a) Defb14, (b) ZNF 51, and (c) Chrm5 genes and top 3 genes (d) Cdh2, (e) Oosp1, and (f) Tth30b downregulated in AhR knock out mice. The data were retrieved from the GEO dataset uploaded by Welle et al (GEO accession 76276). The significance was determined by GEO2R adjusted *P-value < .05. **P-value < .001 (n = 5-6).
Figure 7.
Figure 7.
Identification of novel bone-related genes involved in AhR signaling: GEO2R study (Old AhR KO vs Old Floxed AhR) showing elevated levels of (a) Cdk7, (b) Rassf5, and (c) Eed genes and top 3 genes (d) Hp, (e) Rnf114, and (f) Rab27b downregulated in AhR knock out mice. The data were retrieved from the GEO dataset uploaded by Welle et al (GEO accession 76276). The significance was determined by GEO2R adjusted *P-value < .05. **P-value < .001 (n = 5-6).
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