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

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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.
Jameel Iqbal , Li Sun , Jay Cao , Tony Yuen , Ping Lu , Itai Bab , N. Adrian Leu , Satish Srinivasan , Sagie Wagage , Christopher A. Hunter , Daniel W. Nebert , Mone Zaidi , Narayan G. Avadhani
Journal title changed from 'Proceedings of the National Academy of Sciences'
Proceedings of the National Academy of Sciences of the United States of America 2013 7 2 v.110 no.27
National Academy of Sciences
Journal Articles, USDA Authors, Peer-Reviewed
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