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Cited by 51Oral and gingival health researchOral microbiology and periodontitis researchOral Health Pathology and Treatment

On the Cellular and Molecular Mechanisms of Drug-Induced Gingival Overgrowth

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Ramírez-Rámiz, Albert, Brunet-LLobet, Lluís, Lahor-Soler, Eduard, Miranda-Rius, Jaume·2017·The Open Dentistry Journal
DOI 10.2174/1874210601711010420PMC PMC5564016
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Abstract

Introduction: Gingival overgrowth has been linked to multiple factors such as adverse drug effects, inflammation, neoplastic processes, and hereditary gingival fibromatosis. Drug-induced gingival overgrowth is a well-established adverse event. In early stages, this gingival enlargement is usually located in the area of the interdental papilla. Histologically, there is an increase in the different components of the extracellular matrix. Objective: The aim of this manuscript is to describe and analyze the different cellular and molecular agents involved in the pathogenesis of Drug-induced gingival overgrowth. Method: A literature search of the MEDLINE/PubMed database was conducted to identify the mechanisms involved in the process of drug-induced gingival overgrowth, with the assistance of a research librarian. We present several causal hypotheses and discuss the advances in the understanding of the mechanisms that trigger this gingival alteration. Results: In vitro studies have revealed phenotypic cellular changes in keratinocytes and fibroblasts and an increase of the extracellular matrix with collagen and glycosaminoglycans. Drug-induced gingival overgrowth confirms the key role of collagenase and integrins, membrane receptors present in the fibroblasts, due to their involvement in the catabolism of collagen. The three drug categories implicated: calcineuron inhibitors (immunosuppressant drugs), calcium channel blocking agents and anticonvulsant drugs appear to present a multifactorial pathogenesis with a common molecular action: the blockage of the cell membrane in the Ca2+/Na+ ion flow. The alteration of the uptake of cellular folic acid, which depends on the regulated channels of active cationic transport and on passive diffusion, results in a dysfunctional degradation of the connective tissue. Certain intermediate molecules such as cytokines and prostaglandins play a role in this pathological mechanism. The concomitant inflammatory factor encourages the appearance of fibroblasts, which leads to gingival fibrosis. Susceptibility to gingival overgrowth in some fibroblast subpopulations is due to phenotypic variability and genetic polymorphism, as shown by the increase in the synthesis of molecules related to the response of the gingival tissue to inducing drugs. The authors present a diagram depicting various mechanisms involved in the pathogenesis of drug-induced gingival overgrowth. Conclusion: Individual predisposition, tissue inflammation, and molecular changes in response to the inducing drug favor the clinical manifestation of gingival overgrowth.

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  • FOXO-1 enhances production of TGF-β contributing to gingival overgrowth.

    “FOXO-1 enhances the production of TGF-β contributing to gingival overgrowth.”

    From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [73]

    The Extracellular Matrix section links TGF-β to fibroblast proliferation and extracellular-matrix accumulation in cyclosporine-associated gingival overgrowth. It does not say that FOXO-1 enhances TGF-β production; searches for FOXO-1 and forkhead box O1 found no passage establishing that link. No page number was supplied for the indexed passage. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Phenytoin inhibits FOXO-1.

    “Phenytoin is known to inhibit FOXO-1 [72, 73].”

    From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [73]

    The Immunity Changes and Inflammation and Oxidative Stress sections discuss effects of phenytoin, but neither links it to FOXO-1. Searches for “FOXO-1 phenytoin inhibits” and “forkhead box O1 FOXO1 inhibition phenytoin” found no passage addressing that mechanism. Page numbers were unavailable in our copy. (LLM, conf=0.72)

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Cited by

Sorted by citations

Authors
Ramírez-Rámiz, A., Brunet-LLobet, L., Lahor-Soler, E., & Miranda-Rius, J.
Venue
The Open Dentistry Journal
Publisher
Bentham Science Publishers Ltd.
Published
2017-07-31
Volume
11
Issue
1
Pages
420-435
ISSN
1874-2106 (ISSN-L)
DOI
10.2174/1874210601711010420
PMC
PMC5564016
OpenAlex
W2733141267
Cited by
51
References
2
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 4
FWCI
7.76
Type
journal article
Language
en
Open access
Licence
Locations
  • The Open Dentistry Journal (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
Topics
  • Health Sciences › Health Professions › Pharmacy › Oral and gingival health research
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Dentistry › Periodontics › Oral Health Pathology and Treatment
Keywords
drug-induced gingival hyperplasia, pathogenesis, calcineurin inhibitors, calcium channel blockers, antiepileptic drugs, extracellular matrix, collagen, glycosaminoglycans, collagenase, integrins, fibroblasts, keratinocytes, cytokines, prostaglandins, gingival fibrosis, genetic polymorphism, interdental papilla

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