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

Author:
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
Source:
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.27 pp. 11115-11120
ISSN:
0027-8424
Subject:
enzymes, bone density, carcinogens, receptors, binding proteins, gene expression, bone marrow, toxins, tetrachlorodibenzo-p-dioxin, transcription factors, smoke, cell culture, risk factors, bone formation, cytochrome P-450, mice, osteoporosis, bone resorption, benzopyrenes, pathophysiology, osteoclasts, therapeutics
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.
Agid:
58061
Handle:
10113/58061