Pleiotropic roles of Ca+2/calmodulin-dependent pathways in regulating cadmium-induced toxicity in human osteoblast-like cell lines

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.

Electronic cigarette liquid exposure induces flavor‐dependent osteotoxicity and increases expression of a key bone marker, collagen type I

“…The human osteosarcoma cell lines Saos-2 and MG-63 were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA) and maintained using established culture conditions (Arbon, Christensen, Harvey, & Heggland, 2012;Coonse, Coonts, Morrison, & Heggland, 2007;Ha, Burwell, Goodwin, Noeker, & Heggland, 2016;Smith et al, 2009). Briefly, Saos-2 cells were cultured in McCoy's 5A medium and MG-63 cells in minimal Eagle's medium (EMEM), each supplemented with 10% fetal bovine serum (Atlanta Biologicals, Lawrenceville, GA, USA), 2 mM L-glutamine, 100 IU/mL penicillin and 100 μg/mL streptomycin (Sigma-Aldrich, St. Louis, MO, USA).…”

Anti-Osteogenic Activity of Cadmium in Zebrafish

“…The bending of the newly formed rays that we observed in adult zebrafish exposed to cadmium suggests a reduction of bone stiffness and the impairment of bone mechanical properties. Comparable phenotypes were observed in humans exposed to cadmium throughout the world [5], although the most striking example is probably the itai-itai disease [20]. In this case, the population of a Japanese village was exposed for many years to cadmium through the poisoning, by mining activities, of the river used to water the rice plantations or for fishing.…”

“…Since the cadmium present in the aquatic environment can enter food webs involving aquatic animals important for human diets (e.g., mollusks, fish, and crustaceans) it represents a threat to human health. In this regard, cases of cadmium poisoning have already been reported in humans and were associated with an osteoporosis-like phenotype; a striking example is the itai-itai disease [20]. Several recent studies have further evidenced the potential of cadmium to impair bone formation, mineralization, and remodeling.…”

“…In rats, the consumption of 1 mg/L of cadmium chloride (CdCl 2 ) in drinking water for 24 months affected bone remodeling by decreasing alkaline phosphatase activity and increasing serum levels of C-terminal cross-linking telopeptide of type I collagen [24]. In humans, cadmium poisoning was associated with an osteoporosis-like phenotype and an increased risk of fractures [20,25]. Among signaling pathways involved in the transduction of cadmium-induced osteotoxicity in mammals, the MAPK/ERK pathway has been associated with osteoblast inhibition [26,27], while both canonical and non-canonical Wnt/β-catenin pathways have been implicated in altered bone homeostasis [22].…”

Hybrid silica aerogel nanocomposite adsorbents designed for Cd(II) removal from aqueous solution

“…Due to its great tendency to substitute the essential mineral zinc in the liver and kidneys, accumulated Cd in high amount is deposited and preserved in these organs (Huang et al, ). Also, Cd can lead to serious damages such as cancer, emphysema to the kidneys and liver, bone disorders, testicular atrophy, and hypertension (Duan et al, ; Ha, Burwell, Goodwin, Noeker, & Heggland, ; Tian et al, ). It can attach to the sulfhydryl group of protein to inhibit the enzyme activities.…”