Biological roles of KGF, CTGF and TGF-β in cyclosporine-A- and phenytoin- induced gingival overgrowth: A comparative experimental animal study

Al-hamilly, Nadia Saeed; Radwan, Lobna R.S.; Abdulrahman, Mohamed; Mourad, Mohamed I.; Grawish, Mohammed E.

doi:10.1016/j.archoralbio.2016.02.006

Cited by 10 publications

(8 citation statements)

References 26 publications

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“…23,24 TGF-β has also been implicated in the development of GO in patients and DIGO in animal models. [25][26][27] However, since TGF-β plays an important role in the maintenance of biological homeostasis and developmental processes, difficulties are associated with its direct inhibition, although its toxicity has been significantly attenuated. 28 Therefore, a more detailed understanding of the mechanisms downstream of TGF-β that result in DIGO will contribute to the development of therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

“…A number of inflammatory cytokines have been shown to play a role in periodontitis, and high expression levels of TGF‐β have been observed in the gingival tissue of patients with periodontitis 23,24 . TGF‐β has also been implicated in the development of GO in patients and DIGO in animal models 25‐27 . However, since TGF‐β plays an important role in the maintenance of biological homeostasis and developmental processes, difficulties are associated with its direct inhibition, although its toxicity has been significantly attenuated 28 .…”

Section: Discussionmentioning

confidence: 99%

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The role of nuclear receptor 4A1 (NR4A1) in drug‐induced gingival overgrowth

et al. 2021

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Drug‐induced gingival overgrowth (DIGO) is a side effect of cyclosporine A (CsA), nifedipine (NIF), and phenytoin (PHT). Nuclear receptor 4A1 (NR4A1) plays a role in fibrosis in multiple organs. However, the relationship between NR4A1 and DIGO remains unclear. We herein investigated the involvement of NR4A1 in DIGO. In the DIGO mouse model, CsA inhibited the up‐regulation of Nr4a1 expression induced by periodontal disease (PD) in gingival tissue, but not that of Col1a1 and Pai1. We detected gingival overgrowth (GO) in Nr4a1 knock out (KO) mice with PD. A NR4A1 agonist inhibited the development of GO in DIGO model mice. TGF‐β increased Col1a1 and Pai1 expression levels in KO mouse gingival fibroblasts (mGF) than in wild‐type mice, while the overexpression of NR4A1 in KO mGF suppressed the levels. NR4A1 expression levels in gingival tissue were significantly lower in DIGO patients than in PD patients. We also investigated the relationship between nuclear factor of activated T cells (NFAT) and NR4A1. NFATc3 siRNA suppressed the TGF‐β‐induced up‐regulation of NR4A1 mRNA expression in human gingival fibroblasts (hGF). CsA suppressed the TGF‐β‐induced translocation of NFATc3 into the nuclei of hGF. Furthermore, NIF and PHT also decreased NR4A1 mRNA expression levels and suppressed the translocation of NFATc3 in hGF. We confirmed that CsA, NIF, and PHT reduced cytosolic calcium levels increased by TGF‐β, while CaCl2 enhanced the TGF‐β‐up‐regulated NR4A1 expression. We propose that the suppression of the calcium‐NFATc3‐NR4A1 cascade by these three drugs plays a role in the development of DIGO.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The role of nuclear receptor 4A1 (NR4A1) in drug‐induced gingival overgrowth

et al. 2021

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“…15 The above hormones and cytokines activate gingival fibroblasts (Figure 4). 16 Recent studies suggest that an imbalance between cell proliferation and apoptosis may contribute to CsA-induced gingival hyperplasia. 10 Patients with gingival hyperplasia show an increased prevalence of Porphyromonas gingivalis (P.gingivalis), Treponema denticola and Tannerella forsythia (red complex).…”

Section: Epidemiology and Pathomechanism Of Gingival Hyperplasia Duri...mentioning

confidence: 99%

“…Al‐Hamilly et al Demonstrated that KGF, CTGF, and TGF‐β perform a biological function in the progression of gingival hyperplasia induced by CsA and phenytoin. They concluded that KGF plays a larger role in gingival hyperplasia induced by CsA, while CTGF and TGF‐β in gingival hyperplasia induced by phenytoin 16 …”

Section: Epidemiology and Pathomechanism Of Gingival Hyperplasia Duri...mentioning

confidence: 99%

Cyclosporine‐induced gingival overgrowth—Review

Chojnacka‐Purpurowicz

Wygonowska

Placek

et al. 2022

Dermatologic Therapy

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Drug-induced gingival overgrowth (DIGO) is an undesirable effect resulting from the therapy of one of the three groups of drugs: phenytoin, calcium channel blockers, and cyclosporine A (CsA). It is caused by a fibrous overgrowth leading to gingivitis, periodontitis, and even tooth loss. Possible consequences include tooth decay worsening, pain and difficulty in eating, bleeding gums, and bad breath. The pathomechanism of the hypertrophy is unknown, but there is a correlation between insufficient oral hygiene and the severity of this phenomenon. The gender and age predilection of gingival hyperplasia as a result of CsA therapy is also noticeable. It is most common in children and adolescents of the male sex. The beneficial effect of the removal of tartar and local irritants in reducing the above symptoms has been demonstrated.One of the treatments for DIGO is conventional gingivectomy. The paper is a review article about cyclosporine-induced gingival hyperplasia.

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“…The pathogenesis of DPH and GB induced gingival overgrowth is still unclear: the excessive storage of gingival connective tissue seems to derive from an imbalance between the extracellular matrix (ECM) metabolism (synthesis and degradation) [13]. Some authors suggest that these types of drugs cause a lower degradation of collagen, without an increase in its production [1].…”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Gingival Overgrowth: A Pilot Study on the Effect of Diphenylhydantoin and Gabapentin on Human Gingival Fibroblasts

Lauritano

Moreo

Limongelli

et al. 2020

IJERPH

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Introduction. The administration of several classes of drugs can lead to the onset of gingival overgrowth: anticonvulsants, immunosuppressants, and calcium channel blockers. Among the anticonvulsants, the main drug associated with gingival overgrowth is diphenylhydantoin. Materials and Methods. In this study, we compared the effects of diphenylhydantoin and gabapentin on 57 genes belonging to the “Extracellular Matrix and Adhesion Molecule” pathway, present in human fibroblasts of healthy volunteers. Results. Both molecules induce the same gene expression profile in fibroblasts as well as a significant upregulation of genes involved in extracellular matrix deposition like COL4A1, ITGA7, and LAMB3. The two treatments also induced a significant downregulation of genes involved in the expression of extracellular matrix metalloproteases like MMP11, MMP15, MMP16, MMP24, and transmembrane receptor ITGB4. Conclusions. Data recorded in our study confirmed the hypothesis of a direct action of these drugs at the periodontium level, inducing an increase in matrix production, a reduction in its degradation, and consequently resulting in gingival hyperplasia.

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Biological roles of KGF, CTGF and TGF-β in cyclosporine-A- and phenytoin- induced gingival overgrowth: A comparative experimental animal study

Cited by 10 publications

References 26 publications

The role of nuclear receptor 4A1 (NR4A1) in drug‐induced gingival overgrowth

The role of nuclear receptor 4A1 (NR4A1) in drug‐induced gingival overgrowth

Cyclosporine‐induced gingival overgrowth—Review

Drug-Induced Gingival Overgrowth: A Pilot Study on the Effect of Diphenylhydantoin and Gabapentin on Human Gingival Fibroblasts

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