Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes
Open accessAbstract
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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TCDD administration was unable to stimulate osteoclastogenesis in bone marrow macrophages from CYP1A1/CYP1A2 double knockout and CYP1A1/CYP1A2/CYP1B1 triple knockout mice, unlike in bone marrow macrophages from wild-type mice.
“Moreover, TCDD administration was unable to stimulate osteoclastogenesis in bone marrow macrophages (BMMs) from CYP1A1/CYP1A2 double knockout and CYP1A1/CYP1A2/CYP1B1 triple knockout mice, unlike in BMM from wild-type mice [33].”
From An Overlooked Bone Metabolic Disorder: Cigarette Smoking-Induced Osteoporosis (2022) · cites this paper as [33]
BaP and TCDD in cigarette smoke caused AhR activation and a significant increase in CYP1A1 and CYP1A2 expression, resulting in enhanced osteoclast differentiation and compromised bone mass in wild-type mice but not in AhR-/- mice.
“Jameel et al. reported that BaP and TCDD in cigarette smoke caused AhR activation and a significant increase in CYP1A1 and CYP1A2 expression, resulting in enhanced OC differentiation and compromised bone mass in wild-type mice but not in AhR-/- mice [33].”
From An Overlooked Bone Metabolic Disorder: Cigarette Smoking-Induced Osteoporosis (2022) · cites this paper as [33]
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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
- 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
- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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