Pleiotropic roles of Ca+2/calmodulin-dependent pathways in regulating cadmium-induced toxicity in human osteoblast-like cell lines. (17th October 2016)

• Record Type: Journal Article
• Authors: Ha, Thao T.; Burwell, Shalimar T.; Goodwin, Matthew L.; Noeker, Jacob A.; Heggland, Sara J.
• Is Part Of: Toxicology letters. Volume 260(2016)
• Page Start: 18
• Page End: 27
• Publication Date: 2016-10-17
• Subjects: Cadmium -- Calmodulin -- Osteoblast -- Apoptosis; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2016.08.020
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Identification of pleiotropic roles for CAMK pathways in osteoblast cadmium toxicity. Calmodulin-dependent PDE pathway facilitates cadmium-induced ERK leading to apoptosis. CAMKK plays a protective role against cadmium-induced toxicity via ERK signaling 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 48 h with 5 μM 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.