Cigarette smokers suffer from severe osteoporosis, and are therefore at an exceptionally high risk of skeletal fracture. However, the mechanism through which smoke causes bone loss remains unclear. We find that BaP (benzo[a]pyrene) and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), two of over 200 known chemicals found in cigarette smoke, trigger the aryl hydrocarbon receptor (Ahr) and the cytochrome P450 (Cyp1) enzymes to stimulate bone removal. Despite these observations, several gaps in our understanding remain. First, we are uncertain which bone cell, osteoclast, osteoblast or osteocyte, primarily mediates this action. Therefore, in Specific Aim 1, we will study the bone phenotype of mice in which the Ahr gene is deleted selectively in each cell type, and then examine the effect of the Ahr agonists BaP and TCDD on skeletal mass and remodeling. Second, we are unclear whether the osteoclast-stimulatory action of Ahr agonists involves the activation of mitochondrial or microsomal Cyp1s, and whether the reactive oxygen species (ROS) so produced mediate this action. Therefore, in Specific Aim 2, we will administer BaP and/or TCDD to knock-in mice expressing Cyp1 proteins either in mitochondria or in microsomes. We will phenotype their skeletons and study ROS production in isolated bone marrow cells. Our previous studies have further shown that ROS activate mitochondria-to-nucleus signals to generate a pro-osteoclastogenic footprint comprising CREB, C/EBP?, NF-?B, NFAT2, and hnRNPA2.
In Specific Aim 3, we will determine whether this transcriptional footprint is activated by Ahr agonists. If so, we will utilize siRNA and/or chemical inhibitors to validate the role of each molecule, as well as promoter-reporter assays and ChIP to confirm that the footprint transactivates osteoclast gene expression. These studies should establish the Ahr as a therapeutic target for osteoporosis and unravel, at least to an extent, the molecular basis underlying the osteoporosis noted in smokers.
Smoking cigarettes leads to osteoporosis and a remarkably high propensity to fracture. Several chemical toxins found in cigarette smoke are thought to play a role in causing bone loss, but we are uncertain of the cells they act upon and the molecular events they trigger. This study will use genetically modified mice and traditional pharmacologic approaches to elucidate the precise mechanism through which smoke toxins cause osteoporosis.
| Zaidi, Mone; New, Maria I; Blair, Harry C et al. (2018) Actions of pituitary hormones beyond traditional targets. J Endocrinol 237:R83-R98 |
| Ji, Yaoting; Liu, Peng; Yuen, Tony et al. (2018) Epitope-specific monoclonal antibodies to FSH? increase bone mass. Proc Natl Acad Sci U S A 115:2192-2197 |
| Iqbal, Jameel; Yuen, Tony; Kim, Se-Min et al. (2018) Opening windows for bone remodeling through a SLIT. J Clin Invest 128:1255-1257 |
| Zaidi, Mone; Lizneva, Daria; Kim, Se-Min et al. (2018) FSH, Bone Mass, Body Fat, and Biological Aging. Endocrinology 159:3503-3514 |
| Zaidi, Mone; Yuen, Tony; Sun, Li et al. (2018) Regulation of Skeletal Homeostasis. Endocr Rev 39:701-718 |
| Khattab, Ahmed; Haider, Shozeb; Kumar, Ameet et al. (2017) Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11?-hydroxylase deficiency. Proc Natl Acad Sci U S A 114:E1933-E1940 |
| Chowdhury, A Roy; Long, A; Fuchs, S Y et al. (2017) Mitochondrial stress-induced p53 attenuates HIF-1? activity by physical association and enhanced ubiquitination. Oncogene 36:397-409 |
| Baliram, Ramkumarie; Latif, Rauf; Zaidi, Mone et al. (2017) Expanding the Role of Thyroid-Stimulating Hormone in Skeletal Physiology. Front Endocrinol (Lausanne) 8:252 |
| Sepuri, Naresh B V; Angireddy, Rajesh; Srinivasan, Satish et al. (2017) Mitochondrial LON protease-dependent degradation of cytochrome c oxidase subunits under hypoxia and myocardial ischemia. Biochim Biophys Acta Bioenerg 1858:519-528 |
| Yau, Mabel; Haider, Shozeb; Khattab, Ahmed et al. (2017) Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11?-hydroxysteroid dehydrogenase type 2 deficiency. Proc Natl Acad Sci U S A 114:E11248-E11256 |
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