Cadmium accelerates autophagy of osteocytes by inhibiting the PI3K/AKT/mTOR signaling pathway

Author:

Song Ruilong123,He Shuangjiang12ORCID,Cao Ying12,Lu Yicheng12,Peng Yunwen12,Zou Hui12ORCID,Tong Xishuai12,Ran Di12,Ma Yonggang12,Liu Zongping12ORCID

Affiliation:

1. College of Veterinary Medicine Yangzhou University Yangzhou People's Republic of China

2. Jiangsu Co‐innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou People's Republic of China

3. Guangling College Yangzhou University Yangzhou People's Republic of China

Abstract

AbstractCadmium (Cd) can damage bone cells and cause osteoporosis. Osteocytes are the most numerous bone cells and also important target cells for Cd‐induced osteotoxic damage. Autophagy plays important role in the progression of osteoporosis. However, osteocyte autophagy in Cd‐induced bone injury is not well characterized. Thus, we established a Cd‐induced bone injury model in BALB/c mice and a cellular damage model in MLO‐Y4 cells. Aqueous Cd exposure for 16 months showed an increase in plasma alkaline phosphatase (ALP) activity and increase in urine calcium (Ca) and phosphorus (P) concentrations in vivo. Moreover, expression level of autophagy‐related microtubule‐associated protein 1A/1B‐light chain 3 II (LC3II) and autophagy‐related 5 (ATG5) proteins were induced, and the expression of sequestosome‐1 (p62) was reduced, along with Cd‐induced trabecular bone damage. In addition, Cd inhibited the phosphorylation of mammalian target of rapamycin (mTOR), protein kinase B (AKT), and phosphatidylinositol 3‐kinase (PI3K). In vitro, 80 μM Cd concentrations exposure upregulated LC3II protein expression, and downregulated of p62 protein expression. Similarly, we found that treatment with 80 μM Cd resulted in a reduction in the phosphorylation levels of mTOR, AKT, and PI3K. Further experiments revealed that addition of rapamycin, an autophagy inducer, enhanced autophagy and alleviated the Cd‐induced damage to MLO‐Y4 cells. The findings of our study reveal for the first time that Cd causes damage to both bone and osteocytes, as well as induces autophagy in osteocytes and inhibits PI3K/AKT/mTOR signaling, which could be a protective mechanism against Cd‐induced bone injury.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Jiangsu Province

Publisher

Wiley

Subject

Health, Toxicology and Mutagenesis,Management, Monitoring, Policy and Law,Toxicology,General Medicine

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