NaF Activates MAPKs and Induces Apoptosis in Odontoblast-like Cells

Abstract

The cytotoxic effects of fluoride on odontoblasts are not clear. In this study, we examined whether NaF induces apoptosis in MDPC-23 odontoblast-like cells and the involvement of mitogen-activated protein kinase (MAPK) signaling pathways in NaF-induced apoptosis. MDPC-23 cells incubated with 5 mM NaF for 24 hrs exhibited caspase-3 activation, cleavage of poly(ADP-ribose) polymerase, DNA fragmentation, and an increase in cytoplasmic nucleosomes. Prior to the induction of apoptosis, all MAPKs examined were phosphorylated, but in a different manner. In contrast to the sustained phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38, NaF exposure induced a biphasic phosphorylation of extracellular signal-regulated protein kinase (ERK). NaF-induced apoptosis was markedly suppressed by treatment with the JNK inhibitor, SP600125, and mildly suppressed by the MAPK/ERK kinase inhibitor, U0126. Inhibition of p38 activity did not protect cells from apoptosis. Thus, exposure to NaF induces apoptosis in odontoblast-like cells, depending on JNK and, less significantly, ERK pathways.

Pharmacological and toxicological effects of co-exposure of human gingival fibroblasts to silver nanoparticles and sodium fluoride

“…18,38 In addition, F could also induce the activation of JNK and p42/44 MAPK in osteoclast cells. 6,7 Our studies show that both AgNPs and F significantly increased the phosphorylation of p42/p44 and this effect is enhanced during co-exposure to both xenobiotics. Therefore, the activation of different MAPK by AgNPs and F could be cell dependent.…”

“…On the other hand, F has been shown to be toxic, not only to the skeletal system, but also to the soft tissues by multiple mechanisms, such as enzyme activity inhibition, reactive oxygen and nitrogen species generation, impairment of the antioxidant defense system, induction of inflammation, and apoptosis. [6][7][8][9][10] As AgNPs and F may be used concomitantly in dental practice, we studied the effects of co-exposure to these xenobiotics on human gingival fibroblasts. It is known that xenobiotic interaction may increase or decrease the toxic effect of one or many substances.…”

Fluoride’s Effects on the Formation of Teeth and Bones, and the Influence of Genetics

“…Exposures up to 1 mM of NaF failed to induce stressresponse RNAs or initiate apoptosis in the mouse odontoblast cell line M06-G3 (Wurtz et al, 2008), whereas 1 mM NaF induced oxidative stress and apoptosis in rat primary hippocampal neurons (M Zhang et al, 2007). Exposures in the 5-to 10-mM range are required to induce apoptosis in rat thymocytes and human gingival fibroblasts, rat primary lung cells, and in the odontoblast cell line MDPC-23 (Thrane et al, 2001;Matsui et al, 2007;Lee et al, 2008;Karube et al, 2009), and micromolar NaF leads to apoptosis in neonatal rat osteoblasts and fetal human ameloblast lineage cells (Q Yan et al, 2007;X Yan et al, 2009). Rats exposed to 0, 10, 50, or 100 ppm F ions (approximately 0 to 5.0 mM F ions) in the drinking water over a period of 10 wks demonstrated increases in reactive oxygen species in the blood at 50 ppm and 100 ppm, without evidence of significant oxidative stress within the brain or liver (Chouhan and Flora, 2008).…”

“…Activation of these pathways can Fluoride's Effects on the Formation of Teeth and Bones, and the Influence of Genetics lead to diverse responses, including cell proliferation, differentiation, survival, and apoptosis. Sodium fluoride appears to act predominantly through the Jun N-terminal kinase (JNK) and p38 MAPK signaling pathways (Thrane et al, 2001;Y Zhang et al, 2007;Karube et al, 2009). An alternative MAPK / ERK1 signaling pathway involving an osteoblastic fluoride-sensitive phosphotyrosyl phosphatase (PTP) has been proposed in regard to the mitogenic effects of fluoride (Thomas et al, 1996;Wu et al, 1997;Lau and Baylink, 1998).…”

Molecular Mechanisms of Cytotoxicity and Apoptosis Induced by Inorganic Fluoride

“…For instance, in teeth and bone tissues, micromolar concentrations of fluoride elicit potentially beneficial effects by promoting cell proliferation and growth, whereas millimolar fluoride doses suppress cell proliferation and induce apoptosis. Thus, an exposure to high fluoride doses has been reported to induce apoptotic cell death in ameloblasts [18][19][20], odontoblasts [21], and osteoblasts [22][23][24]. In the cells of other tissues, fluoride has been shown to negatively influence many metabolic, structural, and functional cellular functions in experimental animal models in vivo and in cultured cells in vitro.…”