Transcriptional Analysis Reveals Key Genes in the Pathogenesis of Nifedipine-Induced Gingival Overgrowth

Ju, Yanqin; Huang, Lijuan; Wang, Shuwei; Zhao, Shouliang

doi:10.1155/2020/6128341

Cited by 12 publications

(8 citation statements)

References 53 publications

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“…In 2000, α8 was first reported highly upregulated in lung fibroblasts and HSCs in experimental fibrosis models. Similarly, α8 induction was observed in activated fibroblasts of cardiac fibrosis [64] vascular stenosis [65] , gingival over growth [66]. Due to the prominent upregulation in the lung and liver fibrosis tissues in activated fibroblasts/HSCs, integrin α8β1 was proposed to be a therapeutic target of fibrosis [67].…”

Section: Proposed Contribution Of α8β1 To Fibrosis and Opposing Findingsmentioning

confidence: 98%

“…There are accumulating evidence for myofibroblast differentiation by α11β1 [85] [86] and TGFβ dependent expression of α11 [87,88]. Furthermore, α11 accumulates in fibroblasts/myofibroblasts in the sites of fibrosis, in murine models of the liver, lung and kidney [12] and human gingival overgrowth [66]. In addition, cardiac fibrosis is induced by over-expression of α11 in mice [89].…”

Section: Pathology Specific Integrin α11β1 With a Property Of Collagen Receptormentioning

confidence: 99%

See 1 more Smart Citation

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

Yokosaki¹,

Nishimichi²

2021

Preprint

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Huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare reagent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical reagents.

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Section: Proposed Contribution Of α8β1 To Fibrosis and Opposing Findingsmentioning

confidence: 98%

Section: Pathology Specific Integrin α11β1 With a Property Of Collagen Receptormentioning

confidence: 99%

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

Yokosaki¹,

Nishimichi²

2021

Preprint

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“…In 2000, α8 was first reported for high upregulation at the sites of fibrosis in lung and liver fibrosis [ 64 ]. Similarly, α8 induction was observed in activated fibroblasts in tissues of cardiac fibrosis [ 65 ] vascular stenosis [ 66 ], gingival overgrowth [ 67 ]. Due to the prominent upregulation in the tissues in activated fibroblasts/HSCs, integrin α8β1 was expected to be a new therapeutic target of fibrosis [ 67 ].…”

Section: Pathology Specific Integrin α8β1 With Tgfβ-activating Potentialmentioning

confidence: 99%

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

Yokosaki

Nishimichi

2021

IJMS

View full text Add to dashboard Cite

A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.

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“…TGFB2, a multi-functional TGFB isoform with pro-fibrotic and pro-calcific functions was significantly increased in the mutant CM and cell lysates at the protein and mRNA levels respectively (Table 4 and Figure 3A, blue column). The TGFB2 gene was recently identified as a key factor in drug-induced gingival overgrowth and autocrine TGFb2 signaling could contribute to the pathogenesis of hereditary or pharmacological-induced gingival fibromatosis (23,(35)(36)(37). Additionally, TGFb2 was shown to favor ectopic calcification in various cell types including vascular smooth muscle cells, dermal fibroblasts and trabecular meshwork cells (38,39).…”

Section: Gene Expression Of Differentially Secreted Proteins and Effect Of Tgf Betamentioning

confidence: 99%

“…As such, the hallmark of the disease is pathological deposition of ECM. In drug-induced forms the excessive deposition of ECM was associated with increased levels of TGF-beta (TGFb) a factor known to be involved in both fibrosis and calcification (20)(21)(22)(23). Whether the same pathway is responsible for the gingival phenotype of ERS patients is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach

et al. 2021

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The enamel renal syndrome (ERS) is a rare disorder featured by amelogenesis imperfecta, gingival fibromatosis and nephrocalcinosis. ERS is caused by bi-allelic mutations in the secretory pathway pseudokinase FAM20A. How mutations in FAM20A may modify the gingival connective tissue homeostasis and cause fibromatosis is currently unknown. We here analyzed conditioned media of gingival fibroblasts (GFs) obtained from four unrelated ERS patients carrying distinct mutations and control subjects. Secretomic analysis identified 109 dysregulated proteins whose abundance had increased (69 proteins) or decreased (40 proteins) at least 1.5-fold compared to control GFs. Proteins over-represented were mainly involved in extracellular matrix organization, collagen fibril assembly, and biomineralization whereas those under-represented were extracellular matrix-associated proteins. More specifically, transforming growth factor-beta 2, a member of the TGFβ family involved in both mineralization and fibrosis was strongly increased in samples from GFs of ERS patients and so were various known targets of the TGFβ signaling pathway including Collagens, Matrix metallopeptidase 2 and Fibronectin. For the over-expressed proteins quantitative RT-PCR analysis showed increased transcript levels, suggesting increased synthesis and this was further confirmed at the tissue level. Additional immunohistochemical and western blot analyses showed activation and nuclear localization of the classical TGFβ effector phospho-Smad3 in both ERS gingival tissue and ERS GFs. Exposure of the mutant cells to TGFB1 further upregulated the expression of TGFβ targets suggesting that this pathway could be a central player in the pathogenesis of the ERS gingival fibromatosis.In conclusion our data strongly suggest that TGFβ -induced modifications of the extracellular matrix contribute to the pathogenesis of ERS. To our knowledge this is the first proteomic-based analysis of FAM20A-associated modifications.

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Transcriptional Analysis Reveals Key Genes in the Pathogenesis of Nifedipine-Induced Gingival Overgrowth

Cited by 12 publications

References 53 publications

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach

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