Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts

Hisa Yamada, Fusanori Nishimura, Koji Naruishi, Hsin Hua Chou, Shogo Takashiba, George M. Albright, Salvador Nares, Anthony M. Iacopino, Yoji Murayama

Research output: Contribution to journalArticle

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Abstract

Background: Fibroblasts are known not only to synthesize and secrete extracellular matrix proteins, but also to degrade them for connective tissue remodeling. Drug-induced gingival overgrowth is characterized by a massive accumulation of extracellular matrix components in gingival connective tissues. Although some previous reports suggested that causative drugs stimulated the fibroblast proliferation, the results are not conclusive yet. In this study, we hypothesized that drug-induced gingival overgrowth could be a consequence of impaired ability of matrix degradation rather than an enhanced proliferation of gingival fibroblasts induced by these drugs. Methods: Normal human gingival fibroblasts were cultured with or without either 20 μg/ml of phenytoin or 200 ng/ml of cyclosporin A. Total RNA and cellular proteins were collected every day for RT-PCR analyses and for measuring lysosomal enzyme activity. In addition, an immunohistochemical study was performed to detect lysosomal enzymes in cells from enlarged gingiva of the patients with phenytoin-induced gingival overgrowth. Results: RT-PCR analyses revealed that these drugs suppressed the expression of MMP-1, TIMP-1, and cathepsin L, but not that of cathepsin B in a time-dependent manner. Then, we measured the activity of lysosomal enzymes and cathepsin B and L. The results indicated that although cathepsin B activity was not observed to be impaired, regardless of the drugs used in these cells, both total and active forms of combined activity of cathepsins B and L were suppressed in a time-dependent manner. Conclusions: The results indicate that, besides suggested effects of these drugs on gingival fibroblasts and/or on accumulated cells in the gingival tissues, extracellular matrix-degrading ability, particularly that by cathepsin L, is also suppressed by cyclosporin A and phenytoin in gingival fibroblasts, and that lysosomal enzyme plays an important role in the pathogenesis of drug-induced gingival hyperplasia.

Original languageEnglish
Pages (from-to)955-960
Number of pages6
JournalJournal of Periodontology
Volume71
Issue number6
Publication statusPublished - Jun 2000

Fingerprint

Cathepsin L
Cathepsin B
Tissue Inhibitor of Metalloproteinase-1
Phenytoin
Matrix Metalloproteinases
Cyclosporine
Fibroblasts
Gingival Overgrowth
Pharmaceutical Preparations
Enzymes
Connective Tissue
Extracellular Matrix
Gingival Hyperplasia
Polymerase Chain Reaction
Extracellular Matrix Proteins
Gingiva
RNA

Keywords

  • Cathepsin
  • Cyclosporin A/adverse effects
  • Enzymes, lysosomal
  • Fibroblasts
  • Gingival hyperplasia/pathogenesis
  • Phenytoin/adverse effects
  • Protein, extracellular matrix

ASJC Scopus subject areas

  • Dentistry(all)

Cite this

Yamada, H., Nishimura, F., Naruishi, K., Chou, H. H., Takashiba, S., Albright, G. M., ... Murayama, Y. (2000). Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts. Journal of Periodontology, 71(6), 955-960.

Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts. / Yamada, Hisa; Nishimura, Fusanori; Naruishi, Koji; Chou, Hsin Hua; Takashiba, Shogo; Albright, George M.; Nares, Salvador; Iacopino, Anthony M.; Murayama, Yoji.

In: Journal of Periodontology, Vol. 71, No. 6, 06.2000, p. 955-960.

Research output: Contribution to journalArticle

Yamada, H, Nishimura, F, Naruishi, K, Chou, HH, Takashiba, S, Albright, GM, Nares, S, Iacopino, AM & Murayama, Y 2000, 'Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts', Journal of Periodontology, vol. 71, no. 6, pp. 955-960.
Yamada, Hisa ; Nishimura, Fusanori ; Naruishi, Koji ; Chou, Hsin Hua ; Takashiba, Shogo ; Albright, George M. ; Nares, Salvador ; Iacopino, Anthony M. ; Murayama, Yoji. / Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts. In: Journal of Periodontology. 2000 ; Vol. 71, No. 6. pp. 955-960.
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abstract = "Background: Fibroblasts are known not only to synthesize and secrete extracellular matrix proteins, but also to degrade them for connective tissue remodeling. Drug-induced gingival overgrowth is characterized by a massive accumulation of extracellular matrix components in gingival connective tissues. Although some previous reports suggested that causative drugs stimulated the fibroblast proliferation, the results are not conclusive yet. In this study, we hypothesized that drug-induced gingival overgrowth could be a consequence of impaired ability of matrix degradation rather than an enhanced proliferation of gingival fibroblasts induced by these drugs. Methods: Normal human gingival fibroblasts were cultured with or without either 20 μg/ml of phenytoin or 200 ng/ml of cyclosporin A. Total RNA and cellular proteins were collected every day for RT-PCR analyses and for measuring lysosomal enzyme activity. In addition, an immunohistochemical study was performed to detect lysosomal enzymes in cells from enlarged gingiva of the patients with phenytoin-induced gingival overgrowth. Results: RT-PCR analyses revealed that these drugs suppressed the expression of MMP-1, TIMP-1, and cathepsin L, but not that of cathepsin B in a time-dependent manner. Then, we measured the activity of lysosomal enzymes and cathepsin B and L. The results indicated that although cathepsin B activity was not observed to be impaired, regardless of the drugs used in these cells, both total and active forms of combined activity of cathepsins B and L were suppressed in a time-dependent manner. Conclusions: The results indicate that, besides suggested effects of these drugs on gingival fibroblasts and/or on accumulated cells in the gingival tissues, extracellular matrix-degrading ability, particularly that by cathepsin L, is also suppressed by cyclosporin A and phenytoin in gingival fibroblasts, and that lysosomal enzyme plays an important role in the pathogenesis of drug-induced gingival hyperplasia.",
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T1 - Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts

AU - Yamada, Hisa

AU - Nishimura, Fusanori

AU - Naruishi, Koji

AU - Chou, Hsin Hua

AU - Takashiba, Shogo

AU - Albright, George M.

AU - Nares, Salvador

AU - Iacopino, Anthony M.

AU - Murayama, Yoji

PY - 2000/6

Y1 - 2000/6

N2 - Background: Fibroblasts are known not only to synthesize and secrete extracellular matrix proteins, but also to degrade them for connective tissue remodeling. Drug-induced gingival overgrowth is characterized by a massive accumulation of extracellular matrix components in gingival connective tissues. Although some previous reports suggested that causative drugs stimulated the fibroblast proliferation, the results are not conclusive yet. In this study, we hypothesized that drug-induced gingival overgrowth could be a consequence of impaired ability of matrix degradation rather than an enhanced proliferation of gingival fibroblasts induced by these drugs. Methods: Normal human gingival fibroblasts were cultured with or without either 20 μg/ml of phenytoin or 200 ng/ml of cyclosporin A. Total RNA and cellular proteins were collected every day for RT-PCR analyses and for measuring lysosomal enzyme activity. In addition, an immunohistochemical study was performed to detect lysosomal enzymes in cells from enlarged gingiva of the patients with phenytoin-induced gingival overgrowth. Results: RT-PCR analyses revealed that these drugs suppressed the expression of MMP-1, TIMP-1, and cathepsin L, but not that of cathepsin B in a time-dependent manner. Then, we measured the activity of lysosomal enzymes and cathepsin B and L. The results indicated that although cathepsin B activity was not observed to be impaired, regardless of the drugs used in these cells, both total and active forms of combined activity of cathepsins B and L were suppressed in a time-dependent manner. Conclusions: The results indicate that, besides suggested effects of these drugs on gingival fibroblasts and/or on accumulated cells in the gingival tissues, extracellular matrix-degrading ability, particularly that by cathepsin L, is also suppressed by cyclosporin A and phenytoin in gingival fibroblasts, and that lysosomal enzyme plays an important role in the pathogenesis of drug-induced gingival hyperplasia.

AB - Background: Fibroblasts are known not only to synthesize and secrete extracellular matrix proteins, but also to degrade them for connective tissue remodeling. Drug-induced gingival overgrowth is characterized by a massive accumulation of extracellular matrix components in gingival connective tissues. Although some previous reports suggested that causative drugs stimulated the fibroblast proliferation, the results are not conclusive yet. In this study, we hypothesized that drug-induced gingival overgrowth could be a consequence of impaired ability of matrix degradation rather than an enhanced proliferation of gingival fibroblasts induced by these drugs. Methods: Normal human gingival fibroblasts were cultured with or without either 20 μg/ml of phenytoin or 200 ng/ml of cyclosporin A. Total RNA and cellular proteins were collected every day for RT-PCR analyses and for measuring lysosomal enzyme activity. In addition, an immunohistochemical study was performed to detect lysosomal enzymes in cells from enlarged gingiva of the patients with phenytoin-induced gingival overgrowth. Results: RT-PCR analyses revealed that these drugs suppressed the expression of MMP-1, TIMP-1, and cathepsin L, but not that of cathepsin B in a time-dependent manner. Then, we measured the activity of lysosomal enzymes and cathepsin B and L. The results indicated that although cathepsin B activity was not observed to be impaired, regardless of the drugs used in these cells, both total and active forms of combined activity of cathepsins B and L were suppressed in a time-dependent manner. Conclusions: The results indicate that, besides suggested effects of these drugs on gingival fibroblasts and/or on accumulated cells in the gingival tissues, extracellular matrix-degrading ability, particularly that by cathepsin L, is also suppressed by cyclosporin A and phenytoin in gingival fibroblasts, and that lysosomal enzyme plays an important role in the pathogenesis of drug-induced gingival hyperplasia.

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KW - Phenytoin/adverse effects

KW - Protein, extracellular matrix

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