Cited by 126Bone Metabolism and DiseasesToxic Organic Pollutants ImpactBone health and osteoporosis research

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Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes

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Iqbal, Jameel, Sun, Li, Cao, Jay, Yuen, Tony, Lu, Ping, Bab, Itai, Leu, N. Adrian, Srinivasan, Satish, Wagage, Sagie, Hunter, Christopher A., Nebert, Daniel W., Zaidi, Mone, Avadhani, Narayan G.·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1220919110PMC PMC3704019

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Abstract

Smoking is a major risk factor for osteoporosis and fracture, but the mechanism through which smoke causes bone loss remains unclear. Here, we show that the smoke toxins benzo( a )pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) interact with the aryl hydrocarbon receptor (Ahr) to induce osteoclastic bone resorption through the activation of cytochrome P450 1a/1b (Cyp1) enzymes. BaP and TCDD enhanced osteoclast formation in bone marrow cell cultures and gavage with BaP stimulated bone resorption and osteoclastogenesis in vivo. The osteoclastogenesis triggered by BaP or RANK-L was reduced in Ahr −/− cells, consistent with the high bone mass noted in Ahr −/− male mice. The receptor activator of NF-κB ligand (RANK-L) also failed to induce the expression of Cyp1 enzymes in Ahr −/− cells. Furthermore, the osteoclastogenesis induced by TCDD was lower in Cyp1a1/1a2 −/− and Cyp1a1/1a2/1b1 −/− cultures, indicating that Ahr was upstream of the Cyp enzymes. Likewise, the pharmacological inhibition of the Cyp1 enzymes with tetramethylsilane or proadifen reduced osteoclastogenesis. Finally, deletion of the Cyp1a1 , Cyp1a2 , and Cyp1b1 in triple knockout mice resulted in reduced bone resorption and recapitulated the high bone mass phenotype of Ahr −/− mice. Overall, the data identify the Ahr and Cyp1 enzymes not only in the pathophysiology of smoke-induced osteoporosis, but also as potential targets for selective modulation by new therapeutics.

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Authors: Iqbal, J., Sun, L., Cao, J., Yuen, T., Lu, P., Bab, I., Leu, N. A., Srinivasan, S., Wagage, S., Hunter, C. A., Nebert, D. W., Zaidi, M., & Avadhani, N. G.
Affiliations: University of Pennsylvania (US)
Icahn School of Medicine at Mount Sinai (US)
United States Department of Agriculture (US)
The Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY 10029;
Hebrew University of Jerusalem (IL)
Departments of aAnimal Biology and
Pathobiology, School of Veterinary Medicine, and
University of Cincinnati Medical Center (US)
ORCID: Iqbal, Jameel
Sun, Li
Cao, Jay
Yuen, Tony
Srinivasan, Satish
Hunter, Christopher A.
Zaidi, Mone
Avadhani, Narayan G.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2013-06-17
Volume: 110
Issue: 27
Pages: 11115-11120
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1220919110
PMC: PMC3704019
OpenAlex: W2079795497
Cited by: 126
References: 36
Citations by year: 2026: 5 · 2025: 10 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 8 · 2020: 15 · 2019: 8 · 2018: 12 · 2017: 10 · 2016: 6 · 2015: 11 · 2014: 14 · 2013: 1
FWCI: 4.77
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (R01AG040132, AG-23176, AG40132, R01AG023176)
National Cancer Institute (CA22763, P30CA016520)
National Institute of General Medical Sciences (R01GM034883, GM 34883)
National Institute of Diabetes and Digestive and Kidney Diseases (DK80459, R01DK080459)
National Institute of Environmental Health Sciences (ES014403, P30ES006096, R01ES008147, R01ES014403, P30 ES-06096, ES-08147)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords: smoking, osteoporosis, bone loss, aryl hydrocarbon receptor, benzo[a]pyrene, TCDD, osteoclastogenesis, bone resorption, RANKL, tetramethylsilane, proadifen, bone mass
MeSH terms: Polychlorinated Dibenzodioxins, Animals, Aryl Hydrocarbon Hydroxylases, Benzo(a)pyrene, Bone Resorption, Carcinogens, Disease Models, Animal, Enzyme Induction, Female, Humans, Male, Mice, Inbred C57BL, Smoke, Smoking, Nicotiana, Receptors, Aryl Hydrocarbon, Mice, Knockout, Cytochrome P-450 CYP1A1, Cytochrome P-450 CYP1A2, Mice, Cytochrome P-450 CYP1B1

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Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes

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