TIMP‐1 association with collagen type I overproduction in hereditary gingival fibromatosis

Gawron, Katarzyna; Ochała-Kłos, Anna; Nowakowska, Zuzanna; Bereta, Grzegorz; Łazarz‐Bartyzel, Katarzyna; Grabiec, Aleksander M; Plakwicz, Paweł; Górska, Renata; Fertala, Andrzej; Chomyszyn‐Gajewska, Maria; Potempa, Jan

doi:10.1111/odi.12938

Cited by 22 publications

(16 citation statements)

References 37 publications

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“…However, this function and molecular pathogenesis of REST -associated HGF remain to be elucidated. A significant overexpression of profibrotic genes, including type I collagen, HSP47, TGF-β1, IL-6, CTGF, and TIMP-1, has been demonstrated in HGF gingival fibroblasts compared to controls, while production of proteolytic enzymes, MMP-1 and MMP-2, are reduced (Martelli-Junior et al 2003; Gawron et al 2018). Much evidence has indicated that the contribution of REST repression to basal expression levels is context dependent (Chen et al 1998; Cheong et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Novel REST Truncation Mutations Causing Hereditary Gingival Fibromatosis

et al. 2021

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Hereditary gingival fibromatosis (HGF) is a rare genetic disorder featured by nonsyndromic pathological overgrowth of gingiva. The excessive gingival tissues can cause dental, masticatory, and phonetic problems, which impose severe functional and esthetic burdens on affected individuals. Due to its high recurrent rate, patients with HGF have to undergo repeated surgical procedures of gingival resection, from childhood to adulthood, which significantly compromises their quality of life. Unraveling the genetic etiology and molecular pathogenesis of HGF not only gains insight into gingival physiology and homeostasis but also opens avenues for developing potential therapeutic strategies for this disorder. Recently, mutations in REST (OMIM *600571), encoding a transcription repressor, were reported to cause HGF (GINGF5; OMIM #617626) in 3 Turkish families. However, the functions of REST in gingival homeostasis and pathogenesis of REST-associated HGF remain largely unknown. In this study, we characterized 2 HGF families and identified 2 novel REST mutations, c.2449C>T (p.Arg817*) and c.2771_2793dup (p.Glu932Lysfs*3). All 5 mutations reported to date are nonsenses or frameshifts in the last exon of REST and would presumably truncate the protein. In vitro reporter gene assays demonstrated a partial or complete loss of repressor activity for these truncated RESTs. When coexpressed with the full-length protein, the truncated RESTs impaired the repressive ability of wild-type REST, suggesting a dominant negative effect. Immunofluorescent studies showed nuclear localization of overexpressed wild-type and truncated RESTs in vitro, indicating preservation of the nuclear localization signal in shortened proteins. Immunohistochemistry demonstrated a comparable pattern of ubiquitous REST expression in both epithelium and lamina propria of normal and HGF gingival tissues despite a reduced reactivity in HGF gingiva. Results of this study confirm the pathogenicity of REST truncation mutations occurring in the last exon causing HGF and suggest the pathosis is caused by an antimorphic (dominant negative) disease mechanism.

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Section: Discussionmentioning

confidence: 99%

Novel REST Truncation Mutations Causing Hereditary Gingival Fibromatosis

et al. 2021

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“…Cells were cultured in the presence of 10 μg/ml nystatin until passage 2 to prevent fungal contamination. The isolation procedure and the homogeneity of GF cultures have been standardized and described previously (22). GECs were used for experiments at passage 2 and GFs were used between passages 4 and 9.…”

Section: Methodsmentioning

confidence: 99%

BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients

et al. 2019

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BET bromodomain proteins are important epigenetic regulators of gene expression that bind acetylated histone tails and regulate the formation of acetylation-dependent chromatin complexes. BET inhibitors suppress inflammatory responses in multiple cell types and animal models, and protect against bone loss in experimental periodontitis in mice. Here, we analyzed the role of BET proteins in inflammatory activation of gingival fibroblasts (GFs) and gingival epithelial cells (GECs). We show that the BET inhibitors I-BET151 and JQ1 significantly reduced expression and/or production of distinct, but overlapping, profiles of cytokine-inducible mediators of inflammation and bone resorption in GFs from healthy donors ( IL6, IL8, IL1B, CCL2, CCL5, COX2 , and MMP3 ) and the GEC line TIGK ( IL6, IL8, IL1B, CXCL10, MMP9 ) without affecting cell viability. Activation of mitogen-activated protein kinase and nuclear factor-κB pathways was unaffected by I-BET151, as was the histone acetylation status, and new protein synthesis was not required for the anti-inflammatory effects of BET inhibition. I-BET151 and JQ1 also suppressed expression of inflammatory cytokines, chemokines, and osteoclastogenic mediators in GFs and TIGKs infected with the key periodontal pathogen Porphyromonas gingivalis . Notably, P. gingivalis internalization and intracellular survival in GFs and TIGKs remained unaffected by BET inhibitors. Finally, inhibition of BET proteins significantly reduced P. gingivalis -induced inflammatory mediator expression in GECs and GFs from patients with periodontitis. Our results demonstrate that BET inhibitors may block the excessive inflammatory mediator production by resident cells of the gingival tissue and identify the BET family of epigenetic reader proteins as a potential therapeutic target in the treatment of periodontal disease.

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“…The pathophysiologic mechanisms underpinning HGF remain elusive. Nonetheless, extracellular matrix overproduction involving major component of collagen type I was believed to be a cause of the gingival fibroblast overgrowth phenotype; on the other hand, increased production of TIMP-1 appeared to be associated with excessive collagen I accumulation in HGF fibroblasts [24,25]. Also, Martelli-Junior and coworkers claimed that TGF-β1, IL-6 and perhaps other specific growth factors overproduction in fibroblasts might play pivotal roles in unwarranted collagen I synthesis [26].…”

Section: Figure 1 a Chinese Pedigree With Non-syndromic Hereditary Gingival Fibromatosis (Hgf)mentioning

confidence: 99%

Periodontal Disease Associated with Genetic Disorders

Wu¹,

Leung²,

Sun³

2022

Dentistry

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The object of this chapter was to provide an overview including relevant research progress of some genetic disorders with periodontal manifestations. A number of genetic disorders increase patient susceptibility to periodontal disease, with the latter exhibit rather rapid and aggressive presentations. Periodontal disease, perhaps could be the first detectable sign of an undiagnosed genetic disorder. It is therefore important for dental practitioners to be familiar with genetic disorders and their impact on the periodontal tissues. This chapter reviews several genetic disorders that exhibit periodontal manifestations, including hereditary gingival fibromatosis, Papillon-Lefèvre syndrome, cyclic neutropenia, Ehlers-Danlos syndrome and hypophosphatasia.

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TIMP‐1 association with collagen type I overproduction in hereditary gingival fibromatosis

Cited by 22 publications

References 37 publications

Novel REST Truncation Mutations Causing Hereditary Gingival Fibromatosis

Novel REST Truncation Mutations Causing Hereditary Gingival Fibromatosis

BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients

Periodontal Disease Associated with Genetic Disorders

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