Abstract
Serine/threonine protein kinase C (PKC) is activated by diacylglycerol that is released from membrane lipids by phospholipase C in response to activation of G protein-coupled receptors or receptor tyrosine kinases. PKC isoforms are particularly relevant for proliferation and differentiation of cells including osteoblasts. Osteoblasts/osteocytes produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D handling. PKC activates NFκB, a transcription factor complex controlling FGF23 expression. Here, we analyzed the impact of PKC on FGF23 synthesis. Fgf23 expression was analyzed by qRT-PCR in UMR106 osteoblast-like cells and in IDG-SW3 osteocytes, and FGF23 protein was measured by ELISA. Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA), a PKC activator, up-regulated FGF23 production. In contrast, PKC inhibitors calphostin C, Gö6976, sotrastaurin and ruboxistaurin suppressed FGF23 formation. NFκB inhibitor withaferin A abolished the stimulatory effect of PMA on Fgf23. PKC is a powerful regulator of FGF23 synthesis, an effect which is at least partly mediated by NFκB.
Highlights
Protein kinase C (PKC) isoforms are related serine/threonine kinases probably expressed in all cell types
Three classes of PKC isoforms can be distinguished: classical PKC isoforms are activated by both, diacylglycerol (DAG) and an increase in the intracellular Ca2+ concentration whereas novel PKC isoforms require only DAG, and atypical PKC isoforms are induced by other mechanism [2]
We explored whether PMA-stimulated Fgf23 gene expression translates into enhanced fibroblast growth factor 23 (FGF23) production
Summary
Protein kinase C (PKC) isoforms are related serine/threonine kinases probably expressed in all cell types. PKC activity is induced upon stimulation of various Gq protein-coupled receptors and growth factor receptor tyrosine kinases [1]. Three classes of PKC isoforms can be distinguished: classical PKC (cPKC) isoforms are activated by both, diacylglycerol (DAG) and an increase in the intracellular Ca2+ concentration whereas novel PKC (nPKC) isoforms require only DAG, and atypical PKC (aPKC) isoforms are induced by other mechanism [2]. The classical activation is dependent on phospholipase Cβ or Cγ-mediated breakdown of membrane phosphatidylinositol 4,5-bisphosphate (PIP2) yielding inositol 1,4,5-trisphosphate (IP3) and DAG. IP3 binds the IP3 receptor releasing Ca2+ from the endoplasmic reticulum (ER), while membrane-bound DAG activates PKC [1]. PKC is crucial for most cellular responses including the regulation of gene expression, cell migration, proliferation, differentiation, and apoptosis [3].
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