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Altered fibroblast proliferation and apoptosis in diabetic gingival wounds.

ABSTRACT: Although it is known that diabetes impairs oral wound healing, relatively little is known about the cellular parameters affected, particularly in connective tissue. This study investigated the hypothesis that diabetes impairs connective tissue formation in healing gingiva, and that impaired healing is associated with factors that decrease fibroblast numbers. Full-thickness wounds were created in the palatal gingiva of type 1 and type 2 diabetic and normoglycemic mice. Five days after wounding, diabetic mice had less epithelial wound coverage, less new connective tissue formation, and reduced fibroblast density (p < 0.05). This occurred with increased numbers of caspase-3- and TUNEL-positive fibroblasts, decreased fibroblast proliferation, increased nuclear translocation of the pro-apoptotic transcription factor FOXO1, and increased numbers of polymorphonuclear leukocytes, all of which were significant (p < 0.05). The results suggest that diabetes may decrease fibroblast numbers through increased apoptosis and reduced proliferation, both of which may be mediated through increased activation of FOXO1.

SUBMITTER: Desta T

PROVIDER: S-EPMC3318033 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Altered fibroblast proliferation and apoptosis in diabetic gingival wounds.

Desta T T Li J J Chino T T Graves D T DT

Journal of dental research 20100330 6

Although it is known that diabetes impairs oral wound healing, relatively little is known about the cellular parameters affected, particularly in connective tissue. This study investigated the hypothesis that diabetes impairs connective tissue formation in healing gingiva, and that impaired healing is associated with factors that decrease fibroblast numbers. Full-thickness wounds were created in the palatal gingiva of type 1 and type 2 diabetic and normoglycemic mice. Five days after wounding, d ...[more]

PMID: 20354230

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Project description:Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis-inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs (IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis-infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis-induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.

Dataset Information

Altered fibroblast proliferation and apoptosis in diabetic gingival wounds.

Publications

Altered fibroblast proliferation and apoptosis in diabetic gingival wounds.

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