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Background Cigarette smoking constitutes a major lifestyle risk factor for osteoporosis and hip fracture. It is reported to impair the outcome of many clinical procedures, such as wound infection treatment and fracture healing. Importantly, although several studies have already demonstrated the negative correlation between cigarette consume and impaired bone homeostasis, there is still a poor understanding of how does smoking affect bone health, due to the lack of an adequately designed animal model. Our goal was to determine that cigarette smoke exposure impairs the dynamic bone remodeling process through induction of bone resorption and inhibition of bone formation. Methods We developed cigarette smoke exposure protocols exposing mice to environmental smoking for 10 days or 3 months to determine acute and chronic smoke exposure effects. We used these models, to demonstrate the effect of smoking exposure on the cellular and molecular changes of bone remodeling and correlate these early alterations with subsequent bone structure changes measured by microCT and pQCT. We examined the bone phenotype alterations in vivo and ex vivo in the acute and chronic smoke exposure mice by measuring bone mineral density and bone histomorphometry. Further, we measured osteoclast and osteoblast differentiation gene expression levels in each group. The function changes of osteoclast or osteoblast were evaluated. Results Smoke exposure caused a significant imbalance between bone resorption and bone formation. A 10-day exposure to cigarette smoke sufficiently and effectively induced osteoclast activity, leading to the inhibition of osteoblast differentiation, although it did not immediately alter bone structure as demonstrated in mice exposed to smoke for 3 months. Cigarette smoke exposure also induced DNA-binding activity of nuclear factor kappaB (NFκB) in osteoclasts, which subsequently gave rise to changes in bone remodeling-related gene expression. Conclusions Our findings suggest that smoke exposure induces RANKL activation-mediated by NFκB, which could be a “smoke sensor” for bone remodeling.

Chronic lung inflammation has been associated with an increased risk of lung cancer. However, it is unclear whether such an event affects the incidence of mutations in the K-ras oncogene frequently found in lung tumors and suggested to be involved in lung tumorigenesis. This study investigated potential impacts of inflammation on the incidence of lung tumors and K-ras mutations using a mouse model.FVB/N mice were treated with lipopolysaccharide (LPS) for 16 weeks with or without co-treatment with 4-(methyl-nitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) during the first 4 weeks.There was a significant increase in lung inflammatory responses in mice treated with LPS and with LPS+NNK, compared with mice treated with NNK or with vehicle. The average number of lung tumors per mouse was 3.87 (between 1 and 6) and 0.73 (between 0 and 3) in mice treated with LPS+NNK and NNK alone, respectively (p0.0001). No lung tumors were observed in mice treated with LPS or vehicle. A higher proportion of lung tumors from mice treated with LPS+NNK had K-ras mutations, compared with the mice treated with NNK alone (81.03% versus 45.45%, p0.05).LPS-elicited chronic lung inflammation significantly increases the risk of NNK-mediated lung tumorigenesis in FVB/N mice through K-ras gene activation by point mutations.

Free radicals play a role in aging and age-related human diseases, including pulmonary emphysema. Cigarette smoke represents a source of oxidants and is considered an environmental hazard that causes pulmonary emphysema. Here, we show that caveolin-1 activates ataxia telangiectasia-mutated (ATM) after oxidative stress by sequestering the ATM inhibitor, the catalytic subunit of protein phosphatase 2A, into caveolar membranes. We demonstrate that cigarette smoke extracts promote stress-induced premature senescence in wild type but not caveolin-1 null lung fibroblasts and that caveolin-1 expression is required for activation of the ATM-p53-p21Waf1/Cip1 pathway following stimulation with cigarette smoke extracts in vitro. In vivo studies show that caveolin-1 expression is necessary for cigarette smoking-induced senescence of lung fibroblasts and pulmonary emphysema. These findings bring new insights into the molecular mechanism underlying free radical activation of the ATM-p53 pathway and indicate that caveolin-1 is a novel therapeutic target for the treatment and/or prevention of pulmonary emphysema.