Increased expression of type VI collagen genes in drug‐induced gingival enlargement

Shikata, Hideo; Utsumi, Nobuo; Shimojima, Takahiro; Oda, Yoshio; Okada, Yasunori

doi:10.1016/0014-5793(93)81681-o

Cited by 17 publications

(3 citation statements)

References 26 publications

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“…However, whether this excess matrix accumulation can be solely attributed to the effects of nifedipine and phenytoin alone has been unclear. In gingival tissues isolated from patients diagnosed with nifedipine and phenytoin DIGE, increased pSMAD2/3 nuclear translocation, periostin and fibronectin immunoreactivity, as well as increased collagen density were evident compared to gingiva from healthy individuals confirming previous studies (Takagi et al 1991; Shikata et al 1993; Pisoschi et al 2014). Although only qualitative, staining levels for fibronectin, periostin as well as collagen density seemed higher in phenytoin DIGE compared to nifedipine, which is supported by previous research that phenytoin results in a more fibrotic lesion (Uzel et al 2001).…”

Section: Discussionsupporting

confidence: 86%

Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo

Kim

Michelsons

Creber

et al. 2015

J. Cell Commun. Signal.

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Drug-induced gingival enlargement (DIGE) is a fibrotic condition that can be caused by the antihypertensive drug nifedipine and the anti-seizure drug phenytoin, but the molecular etiology of this type of fibrosis is not well understood and the role of confounding factors such as inflammation remains to be fully investigated. The aim of this study was to develop an ex vivo gingival explant system to allow investigation of the effects of nifedipine and phenytoin alone on human gingival tissue. Comparisons were made to the histology of human DIGE tissue retrieved from individuals with DIGE. Increased collagen, fibronectin, and proliferating fibroblasts were evident, but myofibroblasts were not detected in DIGE samples caused by nifedipine and phenytoin. In healthy gingiva cultured in nifedipine or phenytoin-containing media, the number of cells positive for p-SMAD2/3 increased, concomitant with increased CCN2 and periostin immunoreactivity compared to untreated explants. Collagen content assessed through hydroxyproline assays was significantly higher in tissues cultured with either drug compared to control tissues, which was confirmed histologically. Matrix fibronectin levels were also qualitatively greater in tissues treated with either drug. No significant differences in proliferating cells were observed between any of the conditions. Our study demonstrates that nifedipine and phenytoin activate canonical transforming growth factor-beta signaling, CCN2 and periostin expression, as well as increase collagen density, but do not influence cell proliferation or induce myofibroblast differentiation. We conclude that in the absence of confounding variables, nifedipine and phenytoin alter matrix homeostasis in gingival tissue explants ex vivo, and drug administration is a significant factor influencing ECM accumulation in gingival enlargement.

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Section: Discussionsupporting

confidence: 86%

Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo

Kim

Michelsons

Creber

et al. 2015

J. Cell Commun. Signal.

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“…That study suggested that 10 −7 m nifedipine significantly increased the net deposition of both collagenous and non‐collagenous proteins within the extracellular matrix by fibroblasts derived from normal gingiva following exposure to 10 −7 m nifedipine (29). The mechanism for the altered collagen metabolism possibly involves the effects of nifedipine on collagen gene expression in gingival fibroblasts (30, 31).…”

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confidence: 99%

Synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts exposed to nifedipine and TNF‐alpha in vitro

Johnson

2003

J Oral Pathology Medicine

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“…Recent evidence suggests that 10 ª7 M nifedipine significantly increases deposition of both collagenous and noncollagenous proteins into the extracellular matrix by fibroblasts derived from normal gingiva following exposure to 10 ª7 M nifedipine (24). Nifedipine appears to affect collagen gene expression selectively, as mRNA for type I collagen has been reported to be decreased (25), while mRNA for type IV collagen was increased coincident to exposure of gingival fibroblasts to nifedipine (26).The effect of IL-1 on collagen deposition by fibroblasts into the extracellular matrix is controversial, since reports of increased (27)(28)(29)(30)(31) or decreased (21,32) collagen synthesis coincident to exposure to IL-1 are available. In addition, IL-1 also inhibits collagen accumulation within tissues (33) by stimulation of matrix metalloproteinase expression (34).…”

mentioning

confidence: 99%

Synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts exposed to nifedipine and interleukin‐1‐beta in vitro

Johnson¹,

Zebrowski

Dai

2000

J Oral Pathology Medicine

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Gingival overgrowth commonly occurs coincident to therapy with calcium channel blockers. The biologic mechanism for this condition is unknown; however, many clinicians suggest that poor oral hygiene may contribute to development of the overgrowth. This study tests the hypothesis that collagenous protein synthesis by gingival fibroblasts is synergistically enhanced when they are exposed to both nifedipine (N) and the pro‐inflammatory cytokine, interleukin‐1‐beta, a cytokine expressed in inflamed gingiva. Human gingival fibroblasts were isolated from biopsies of normal gingiva and cells separated into two groups. Group 1 was exposed to media containing 0, 5, 50, or 500 pg/ml IL‐1‐beta, or 10−7 M N for 7 days; Group 2 was exposed to those concentrations of IL‐1‐beta +10−7 M N. [3H]‐proline was added to the medium for the final 24 h. Cells and matrix were harvested and radioactivity determined by liquid scintillation analysis. Means (d.p.m./103 cells) were compared by factorial ANOVA and Scheffè comparisons. Collagenous protein synthesis was significantly reduced by 5 pg/ml IL‐1‐beta +10−7 M N and enhanced by 500 pg/ml IL‐1‐beta +10−7 M N as compared to N or IL‐1‐beta alone. Thus, patients may be more susceptible to gingival overgrowth coincident to nifedipine therapy as a result of the synergistic enhancement of connective tissue synthesis by these agents.

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Increased expression of type VI collagen genes in drug‐induced gingival enlargement

Cited by 17 publications

References 26 publications

Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo

Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo

Synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts exposed to nifedipine and TNF‐alpha in vitro

Synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts exposed to nifedipine and interleukin‐1‐beta in vitro

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