1. Pleiotropic roles of Ca +2 /calmodulin-dependent pathways in regulating cadmium-induced toxicity in human osteoblast-like cell lines.
- Author
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Ha TT, Burwell ST, Goodwin ML, Noeker JA, and Heggland SJ
- Subjects
- Benzimidazoles pharmacology, Benzylamines pharmacology, Biomarkers metabolism, Cadmium agonists, Cadmium chemistry, Calcium-Calmodulin-Dependent Protein Kinase Kinase antagonists & inhibitors, Calcium-Calmodulin-Dependent Protein Kinase Kinase chemistry, Calcium-Calmodulin-Dependent Protein Kinase Type 2 antagonists & inhibitors, Calcium-Calmodulin-Dependent Protein Kinase Type 2 chemistry, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Calmodulin agonists, Calmodulin antagonists & inhibitors, Calmodulin metabolism, Cell Line, Tumor, Cyclic Nucleotide Phosphodiesterases, Type 1 antagonists & inhibitors, Cyclic Nucleotide Phosphodiesterases, Type 1 chemistry, Environmental Pollutants agonists, Environmental Pollutants antagonists & inhibitors, Enzyme Activation drug effects, Humans, Lethal Dose 50, MAP Kinase Signaling System drug effects, Naphthalimides pharmacology, Osteoblasts enzymology, Osteoblasts metabolism, Phosphodiesterase Inhibitors pharmacology, Protein Kinase Inhibitors pharmacology, Sulfonamides pharmacology, Apoptosis drug effects, Cadmium toxicity, Calcium Signaling drug effects, Calcium-Calmodulin-Dependent Protein Kinase Kinase metabolism, Cyclic Nucleotide Phosphodiesterases, Type 1 metabolism, Environmental Pollutants toxicity, Osteoblasts drug effects
- Abstract
The heavy metal cadmium is a widespread environmental contaminant that has gained public attention due to the global increase in cadmium-containing electronic waste. Human exposure to cadmium is linked to the pathogenesis of osteoporosis. We previously reported cadmium induces apoptosis and decreases alkaline phosphatase mRNA expression via extracellular signal-regulated protein kinase (ERK) activation in Saos-2 bone-forming osteoblasts. This study examines the mechanisms of cadmium-induced osteotoxicity by investigating roles of Ca
+2 /calmodulin-dependent protein kinase (CAMK) pathways. Saos-2 or MG-63 cells were treated for 24 or 48h with 5μM CdCl2 alone or in combination with calmodulin-dependent phosphodiesterase (PDE) inhibitor CGS-9343β; calmodulin-dependent kinase kinase (CAMKK) inhibitor STO-609; or calmodulin-dependent kinase II (CAMKII) inhibitor KN-93. CGS-9343β protected against cadmium-induced toxicity and attenuated ERK activation; STO-609 enhanced toxicity and exacerbated ERK activation, whereas KN-93 had no detectable effect on cadmium-induced toxicity. Furthermore, CGS-9343β co-treatment attenuated cadmium-induced apoptosis; but CGS-9343β did not recover cadmium-induced decrease in ALP activity. The major findings suggest the calmodulin-dependent PDE pathway facilitates cadmium-induced ERK activation leading to apoptosis, whereas the CAMKK pathway plays a protective role against cadmium-induced osteotoxicity via ERK signaling. This research distinguishes itself by identifying pleiotropic roles for CAMK pathways in mediating cadmium's toxicity in osteoblasts., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)- Published
- 2016
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