Requirement for active glycogen synthase kinase-3? in TGF-?1 upregulation of connective tissue growth factor (CCN2/CTGF) levels in human gingival fibroblasts.
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ABSTRACT: Connective tissue growth factor (CCN2/CTGF) mediates transforming growth factor-? (TGF-?)-induced fibrosis. Drug-induced gingival overgrowth is tissue specific. Here the role of the phosphoinositol 3-kinase (PI3K) pathway in mediating TGF-?1-stimulated CCN2/CTGF expression in primary human adult gingival fibroblasts and human adult lung fibroblasts was compared. Data indicate that PI3K inhibitors attenuate upregulation of TGF-?1-induced CCN2/CTGF expression in human gingival fibroblasts independent of reducing JNK MAP kinase activation. Pharmacologic inhibitors and small interfering (si)RNA-mediated knockdown studies indicate that calcium-dependent isoforms and an atypical isoform of protein kinase C (PKC-?) do not mediate TGF-?1-stimulated CCN2/CTGF expression in gingival fibroblasts. As glycogen synthase kinase-3? (GSK-3?) can undergo phosphorylation by the PI3K/pathway, the effects of GSK-3? inhibitor kenpaullone and siRNA knockdown were investigated. Data in gingival fibroblasts indicate that kenpaullone attenuates TGF-?1-mediated CCN2/CTGF expression. Activation of the Wnt canonical pathways with Wnt3a, which inhibits GSK-3?, similarly inhibits TGF-?1-stimulated CCN2/CTGF expression. In contrast, inhibition of GSK-3? by Wnt3a does not inhibit, but modestly stimulates, CCN2/CTGF levels in primary human adult lung fibroblasts and is ?-catenin dependent, consistent with previous studies performed in other cell models. These data identify a novel pathway in gingival fibroblasts in which inhibition of GSK-3? attenuates CCN2/CTGF expression. In adult lung fibroblasts inhibition of GSK-3? modestly stimulates TGF-?1-regulated CCN2/CTGF expression. These studies have potential clinical relevance to the tissue specificity of drug-induced gingival overgrowth.
SUBMITTER: Bahammam M
PROVIDER: S-EPMC3761177 | biostudies-literature | 2013 Sep
REPOSITORIES: biostudies-literature
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