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Cadmium (Cd), an environmental pollutant, induces osteoporosis by directly destroying bone tissue, but its direct damaging effect on bone cells is not fully illustrated. Here, we treated mouse bone marrow stem cells (BMSC) and bone marrow macrophages (BMM) with Cd, and gave BALB/c mice Cd in water. Long-term Cd exposure significantly inhibited BMSC osteogenesis and osteoclast differentiation in vitro , and induced osteoporosis in vivo. Cd exposure also reduced P2X7 expression dramatically. However, P2X7 deletion significantly inhibited osteoblast and osteoclast differentiation; P2X7 overexpression obviously reduced the suppression effect of Cd on osteoblast and osteoclast differentiation. The suppression of P2X7–PI3K–AKT signaling aggravated the effect of Cd. In mice, short-term Cd exposure did not result in osteoporosis, but bone formation was inhibited, RANKL expression was increased, and osteoclasts were significantly increased in vivo. In vitro , short-term Cd exposure not only increased osteoclast numbers, but also promoted osteoclast adhesion function at late-stage osteoclast differentiation. Cd exposure also reduced P2X7 expression in vivo and in vitro. Our results demonstrate that short-term Cd exposure does not affect osteoblast and osteoclast apoptosis in vivo and in vitro , but long-term Cd exposure significantly increases bone tissue apoptosis. Overall, our results describe a novel mechanism for Cd-induced osteoporosis. ga1 • Long-term Cd exposure induced osteoporosis in mice. • Cd exposure decreased P2X7 greatly in vitro and in vivo. • In vitro , deleting P2X7 inhibited osteoblast and osteoclast differentiation. • Cd exposure inhibited osteogenesis and osteoclast differentiation in vitro. • P2X7 overexpression decreased this suppressive effect of Cd. [ABSTRACT FROM AUTHOR]

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 ([Ca2+] i). Cd-induces the elevation of [Ca2+] i and activation of CaM/CaMKII/CaMKIV signaling. CaM/CaMKII/CaMKIV signaling induces the expression of NFATc1, leading to osteoclast differentiation. ER Ca2+ release, the elevation of [Ca2+] I , and the activation of CaM, CaMKII, and CaMKIV can be inhibited by 2-APB, BAPTA-AM, W-7, KN93 and STO-609, respectively. 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. [ABSTRACT FROM AUTHOR]