Dataset Information

Bisphosphonates induce senescence in normal human oral keratinocytes.

ABSTRACT: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) commonly occurs in individuals receiving bisphosphonates (BPs) with clinical manifestations of the exposed necrotic bone. Although defective wound healing of soft tissue is frequently, if not always, observed in BRONJ, the effects of BPs on oral soft tissue or cells remain unknown. To investigate the effects of BPs on cells of oral mucosal tissue, we studied the effect of pamidronate (PAM), one of the BPs most commonly administered to cancer patients, on the phenotypes of normal human oral keratinocytes (NHOK) and fibroblasts (NHOF). When exposed to PAM at 10 µM, NHOK, not NHOF, underwent senescence: NHOK overexpressed senescence-associated ?-galactosidase (SA-?-Gal), p16INK4A, IL-6, and IL-8. When exposed to a higher level (50 µM) of PAM, NHOK maintained senescent phenotypes, but NHOF underwent apoptosis. PAM-induced senescence in NHOK is mediated, in part, via geranylgeranylation of the mevalonate pathway. Our in vitro 3D oral mucosal tissue construction studies further demonstrated that PAM induced senescence and impaired re-epithelialization of oral mucosa. Analysis of these data indicates that premature senescence of oral mucosal cells and subsequent defective soft-tissue wound healing might be partly responsible for the development of BRONJ in individuals receiving PAM or other BPs.

SUBMITTER: Kim RH

PROVIDER: S-EPMC3144120 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bisphosphonates induce senescence in normal human oral keratinocytes.

Kim R H RH Lee R S RS Williams D D Bae S S Woo J J Lieberman M M Oh J-E JE Dong Q Q Shin K-H KH Kang M K MK Park N-H NH

Journal of dental research 20110322 6

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) commonly occurs in individuals receiving bisphosphonates (BPs) with clinical manifestations of the exposed necrotic bone. Although defective wound healing of soft tissue is frequently, if not always, observed in BRONJ, the effects of BPs on oral soft tissue or cells remain unknown. To investigate the effects of BPs on cells of oral mucosal tissue, we studied the effect of pamidronate (PAM), one of the BPs most commonly administered to cance ...[more]

PMID: 21427353

Similar Datasets

Project description:BACKGROUND: Epidemiological data show that the incidence of carcinomas in humans is highly dependent on age. However, the initial steps of the age-related molecular oncogenic processes by which the switch towards the neoplastic state occurs remain poorly understood, mostly due to the absence of powerful models. In a previous study, we showed that normal human epidermal keratinocytes (NHEKs) spontaneously and systematically escape from senescence to give rise to pre-neoplastic emerging cells. METHODS: Here, this model was used to analyze the gene expression profile associated with the early steps of age-related cell transformation. We compared the gene expression profiles of growing or senescent NHEKs to post-senescent emerging cells. Data analyses were performed by using the linear modeling features of the limma package, resulting in a two-sided t test or F-test based on moderated statistics. The p-values were adjusted for multiple testing by controlling the false discovery rate according to Benjamini Hochberg method.The common gene set resulting of differential gene expression profiles from these two comparisons revealed a post-senescence neoplastic emergence (PSNE) gene signature of 286 genes. RESULTS: About half of these genes were already reported as involved in cancer or premalignant skin diseases. However, bioinformatics analyses did not highlight inside this signature canonical cancer pathways but metabolic pathways, including in first line the metabolism of xenobiotics by cytochrome P450. In order to validate the relevance of this signature as a signature of pretransformation by senescence evasion, we invalidated two components of the metabolism of xenobiotics by cytochrome P450, AKR1C2 and AKR1C3. When performed at the beginning of the senescence plateau, this invalidation did not alter the senescent state itself but significantly decreased the frequency of PSNE. Conversely, overexpression of AKR1C2 but not AKR1C3 increased the frequency of PSNE. CONCLUSIONS: To our knowledge, this study is the first to identify reprogrammation of metabolic pathways in normal keratinocytes as a potential determinant of the switch from senescence to pre-transformation.

Dataset Information

Bisphosphonates induce senescence in normal human oral keratinocytes.

Publications

Bisphosphonates induce senescence in normal human oral keratinocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets