Ca2+/CaM/CaMK signaling is involved in cadmium-induced osteoclast differentiation. (August 2020)

• Record Type: Journal Article
• Authors: Liu, Wei; Le, Chung Chi; Wang, Dong; Ran, Di; Wang, Yi; Zhao, Hongyan; Gu, Jianhong; Zou, Hui; Yuan, Yan; Bian, Jianchun; Liu, Zongping
• Is Part Of: Toxicology. Volume 441(2020)
• Publication Date: 2020-08
• Subjects: Cd cadmium -- RANKL receptor activator of nuclear factor-κ B ligand -- OPG osteoprotegerin -- CaM calmodulin -- CaMK calmodulin-dependent protein kinase -- NFATc1 nuclear factor of activated T-cells, cytoplasmic 1 -- M-CSF macrophage colony-stimulating factor -- TNF tumor necrosis factor -- IL interleukin -- c-Fos cellular oncogene Fos -- NF-κB nuclear factor kappa-B -- TRAF6 tumor necrosis factor receptor-related factor 6 -- CK creatine kinase -- CAII carbonic anhydrase II -- 2-APB 2-Aminoethoxydiphenyl borate -- TRAP tartrate-resistant acid phosphatase -- RT-PCR real-time quantitative PCR -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- RTCA teal-time cell analysis -- α-MEM α-Minimum Essential Medium -- PBS phosphate-buffered saline -- LSCM laser scanning confocal microscope -- CREB cAMP-response element binding protein -- ER endoplasmic reticulum -- BAPTA-AM 1, 2-bis(2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid; Cadmium -- Osteoclast -- Differentiation -- CaM/CaMK pathway -- NFATc1; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2020.152520
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Schematic representation of the proposed Cd-induced signaling pathway in osteoclasts . Treatment of osteoclasts with Cd leads to a transient increase in intracellular calcium concentration ([Ca 2+ ]i ). Cd-induces the elevation of [Ca 2+ ]i and activation of CaM/CaMKII/CaMKIV signaling. CaM/CaMKII/CaMKIV signaling induces the expression of NFATc1, leading to osteoclast differentiation. ER Ca 2+ release, the elevation of [Ca 2+ ]I, and the activation of CaM, CaMKII, and CaMKIV can be inhibited by 2-APB, BAPTA-AM, W-7, KN93 and STO-609, respectively. Abstract: Environmental cadmium (Cd) pollution can ultimately lead to chronic toxicity via food consumption. Previous studies have demonstrated that long-term low-dose Cd exposure decreases bone mineral density and bone mineralization. Cd may increase receptor activator of nuclear factor-κ B ligand (RANKL) expression by osteoclasts, and inhibit the expression of osteoprotegerin. However, the molecular mechanism underlying Cd toxicity toward osteoclasts is unclear. In this study, bone marrow monocytes were isolated from C57BL/6 mice and treated with macrophage colony-stimulating factor and RANKL to induce the formation of osteoclasts. The results show that low-dose Cd exposure induced osteoclast differentiation. Cd also increased the intracellular calcium concentration of osteoclasts by triggering release of calcium ions from the endoplasmic reticulum into the cytoplasm. Furthermore, the elevation of intracellular calcium levels was shown to activate the calmodulin (CaM)/calmodulin-dependent protein kinase (CaMK) pathway. NFATc1 is a downstream protein of CaM/CaMK signaling, as well as a key player in osteoclast differentiation. Overall, we conclude that Cd activates the CaM/CaMK/NFATc1 pathway and regulates osteoclast differentiation by increasing intracellular calcium concentration. Our data provide new insights into the mechanisms underlying osteoclast differentiation following Cd exposure. This study provides a theoretical basis for future investigations into the therapeutic application of CaMK inhibitors in osteoporosis induced by Cd exposure.