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  2. Low-dose cadmium exposure promotes osteoclastogenesis by enhancing autophagy via inhibiting the mTOR/p70S6K1 signaling pathway

Low-dose cadmium exposure promotes osteoclastogenesis by enhancing autophagy via inhibiting the mTOR/p70S6K1 signaling pathway

  • Toxicol Lett. 2022 Aug 15;367:9-18. doi: 10.1016/j.toxlet.2022.07.005.
Zhaojie Wang 1 Dongli Li 1 Lijun Mo 1 Shujun Liang 1 Xuemei Liao 1 Sihui Guo 1 Xingfen Yang 2 Qinzhi Wei 3
Affiliations

Affiliations

  • 1 School of Public Health, Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou 510515, PR China.
  • 2 School of Public Health, Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou 510515, PR China. Electronic address: [email protected].
  • 3 School of Public Health, Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou 510515, PR China. Electronic address: [email protected].
Abstract

Cadmium (Cd)-induced bone damage may be mediated through activating osteoclastogenesis. However, the underlying mechanism is unknown. The purpose of this study was to explore the effect and possible mechanism of CdCl2-induced osteoclastogenesis in RAW264.7 cells. We found that a low concentration of CdCl2 (0.025 and 0.050 µM) did not affect the viability of RAW264.7 cells, but promoted osteoclastogenesis. A low concentration of CdCl2 increased the mRNA and protein expression of osteoclastogenesis-related genes. TRAP staining and transmission electron microscopy (TEM) also demonstrated that CdCl2 promoted osteoclastogenesis. A low concentration of CdCl2 upregulated the levels of LC3-II and Beclin-1, and decreased p62 expression. TEM showed relatively abundant autophagic vacuoles (autophagosomes) after CdCl2 exposure. A low concentration of CdCl2 downregulated the expression levels of mTOR and p70S6K1, and the relative protein expression ratios of p-mTOR/mTOR and p-p70S6K1/p70S6K1. When cells were treated with the Autophagy Inhibitor chloroquine (CQ) or mTOR Activator MHY1485 combined with CdCl2, the expressions of osteoclastogenesis related-genes were decreased and Autophagy was attenuated compared with cells treated with CdCl2 alone. Deficiencies in autophagosomes and osteoclasts were also observed. Taken together, the results indicate that a low concentration of CdCl2 promotes osteoclastogenesis by enhancing Autophagy via inhibiting the mTOR/p70S6K1 signaling pathway.

Keywords

Autophagy; Cadmium; MTOR; Osteoclastogenesis.

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