Nicotine-induced CCN2: from Smoking to Periodontal Fibrosis

Takeuchi, Hisashi; Kubota, Satoshi; Murakashi, Etsuko; Zhou, Yueren; Endo, Kentaro; Ng, P.S.; Takigawa, Masaharu; Numabe, Yukihiro

doi:10.1177/0022034509353403

Cited by 32 publications

(27 citation statements)

References 21 publications

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“…In this study, knockdown of CCN2 by CCN2 siRNA strongly reduced the elevated mRNA and protein levels of CCN2 induced by CSE or nicotine and then inhibited the rPASMCs proliferation. These results indicate that CSE and nicotine can induce CCN2 production, which is consistent with other studies [Takeuchi et al, 2010;Wang et al, 2011]. Furthermore, these results reveal that CCN2 plays an important role in the regulation of cigarette smoke-induced rPASMCs proliferation.…”

Section: Discussionsupporting

confidence: 92%

CCN2 promotes cigarette smoke‐induced proliferation of rat pulmonary artery smooth muscle cells through upregulating cyclin D1 expression

Wang

Liu

et al. 2011

J of Cellular Biochemistry

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Cigarette smoke has been demonstrated to induce pulmonary vascular remodeling, which is characterized by medial thickening of the pulmonary arteries mainly resulting from the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs). However, the molecular mechanism underlying this process is still unclear. In the present study, we investigated whether CCN2 regulated rat PASMCs (rPASMCs) proliferation induced by cigarette smoke extract (CSE) and nicotine by upregulating cyclin D1 in vitro. CCN2 siRNA or cyclin D1 siRNA were transfected to rPASMCs which were then exposed to CSE and nicotine. Both mRNA and protein expressions of CCN2 were significantly increased in rPASMCs treated with 2% CSE or 1 µM nicotine, which markedly promoted the proliferation of rPASMCs. CCN2 siRNA inhibited the proliferation of rPASMCs induced by CSE or nicotine. Furthermore, CCN2 siRNA markedly suppressed the mRNA and protein expressions of cyclin D1 in rPASMCs and led to cell cycle arrest in G0/G1 phase resulting in reduced rPASMCs proliferation. These findings suggest that CCN2 contributes to the CSE and nicotine-induced proliferation of rPASMCs at least in part by upregulating cyclin D1 expression.

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Section: Discussionsupporting

confidence: 92%

CCN2 promotes cigarette smoke‐induced proliferation of rat pulmonary artery smooth muscle cells through upregulating cyclin D1 expression

Wang

Liu

et al. 2011

J of Cellular Biochemistry

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“…No patients had taken any antibiotics or anti-inflammatory drugs for 3 months prior to the study. Tissues were obtained according to established procedures [10,19]. Briefly, the gingiva and periodontal ligaments were cut into small pieces.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we cultured human gingival fibroblast cells (HGF) and periodontal ligament (PDL) cells with 1 lg/ml nicotine and found that extracellular matrix (ECM) overproduction could be induced by nicotine stimulation through induction of CCN family protein 2 (CCN2/CTGF) and type I collagen at both RNA and protein levels [10]. In this previous study, we observed nicotine-induced cellular vacuolization and induction of type I collagen that was mediated by the pro-fibrotic molecule CCN2/CTGF, which was confirmed using a neutralizing anti-CTGF antibody.…”

Section: Introductionmentioning

confidence: 99%

Matrix remodeling response of human periodontal tissue cells toward fibrosis upon nicotine exposure

et al. 2014

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It is widely accepted that fibrosis is frequently observed in the gingiva of smokers. However, the mechanisms by which smoking results in pathological changes in periodontal tissue that lead to fibrosis are not entirely clear. Our former report showed that type I collagen synthesis was promoted by nicotine via CCN family protein 2 in human periodontal tissue cells. Here, we evaluated other aspects of nicotine function from a viewpoint of extracellular matrix (ECM) remodeling. Human gingival fibroblasts (n = 4) and periodontal ligament cells (n = 3) were isolated. The cells were treated with nicotine at a variety of concentrations for 12-48 h. Modulators of matrix remodeling were measured using enzyme-linked immunosorbent assays. Cell migration and morphology were also evaluated. As a result, following treatment with 1 μg/ml nicotine, tissue inhibitor of metalloproteinase-1 and transforming growth factor-β1 production in both cell lysates and supernatants, and matrix metalloproteinases-1 production in cell lysates, were significantly increased (p < 0.05). Compared to controls, cell migration was significantly inhibited (p < 0.005) by nicotine in a time-dependent manner. Electron microscopic analysis revealed the presence of a number of vacuoles in nicotine-treated cells. These results indicate that nicotine not only impairs fibroblast motility, and induces cellular degenerative changes, but also alters ECM-remodeling systems of periodontal cells. Induction of matrix remodeling molecules, combined with type I collagen accumulation, may account for the molecular mechanism of nicotine-induced periodontal fibrosis.

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“…Nicotine has been reported to increase the production of CTGF protein in human gingival fibroblasts and pulmonary artery smooth muscle cells [8,9]. We hypothesized that maternal nicotine exposure could augment neonatal hyperoxia-induced lung fibrosis in rats.…”

Section: Introductionmentioning

confidence: 99%

Maternal Nicotine Exposure Exacerbates Neonatal Hyperoxia-Induced Lung Fibrosis in Rats

Huang

Chou²,

Lin³

et al. 2014

Neonatology

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Background: Maternal nicotine exposure increases lung collagen in fetal and newborn animals. Connective tissue growth factor (CTGF) plays a role in hyperoxia-induced pulmonary fibrosis. Objective: To determine whether pre- and postnatal nicotine exposure can augment CTGF expression and postnatal hyperoxia-induced lung fibrosis. Methods: Nicotine was administered to pregnant Sprague-Dawley rats at a dose of 6 mg/kg/day from gestational days 7-21 (prenatal nicotine-treated group) and gestational day 7 to postnatal day 14 (pre- and postnatal nicotine-treated group). A control group of pregnant dams was injected with an equal volume of saline. Within 12 h of birth, rats were exposed to room air or 1 week of >95% O₂ and an additional 2 weeks of 60% O₂ (3 weeks of hyperoxia). Lungs were taken for total collagen, CTGF expression and histological analyses. Results: In each maternal treatment group, the rats reared in hyperoxia had a higher total collagen compared with rats reared in room air on postnatal days 7 and 21. Collagen content was significantly higher in rats born to pre- and postnatal nicotine-treated dams than rats born to saline-treated and prenatal nicotine-treated dams on postnatal days 7 and 21. Pre- and postnatal nicotine exposure and neonatal hyperoxia exposure increased CTGF expression on postnatal days 7 and 21. Conclusions: CTGF may be involved in the pathogenesis of lung fibrosis induced by maternal nicotine and neonatal hyperoxia, and maternal nicotine exposure exacerbates neonatal hyperoxia-induced lung fibrosis. These results are relevant to neonates who require supplemental oxygen and are exposed to the breast milk of smoking mothers during infancy.

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Nicotine-induced CCN2: from Smoking to Periodontal Fibrosis

Cited by 32 publications

References 21 publications

CCN2 promotes cigarette smoke‐induced proliferation of rat pulmonary artery smooth muscle cells through upregulating cyclin D1 expression

CCN2 promotes cigarette smoke‐induced proliferation of rat pulmonary artery smooth muscle cells through upregulating cyclin D1 expression

Matrix remodeling response of human periodontal tissue cells toward fibrosis upon nicotine exposure

Maternal Nicotine Exposure Exacerbates Neonatal Hyperoxia-Induced Lung Fibrosis in Rats

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