PMID- 37148155 OWN - NLM STAT- MEDLINE DCOM- 20230706 LR - 20230706 IS - 1522-7278 (Electronic) IS - 1520-4081 (Linking) VI - 38 IP - 8 DP - 2023 Aug TI - Cadmium accelerates autophagy of osteocytes by inhibiting the PI3K/AKT/mTOR signaling pathway. PG - 1980-1988 LID - 10.1002/tox.23823 [doi] AB - Cadmium (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 muM Cd concentrations exposure upregulated LC3II protein expression, and downregulated of p62 protein expression. Similarly, we found that treatment with 80 muM 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. CI - (c) 2023 Wiley Periodicals LLC. FAU - Song, Ruilong AU - Song R AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. AD - Guangling College, Yangzhou University, Yangzhou, People's Republic of China. FAU - He, Shuangjiang AU - He S AUID- ORCID: 0000-0001-8755-8231 AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Cao, Ying AU - Cao Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Lu, Yicheng AU - Lu Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Peng, Yunwen AU - Peng Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Zou, Hui AU - Zou H AUID- ORCID: 0000-0003-2637-3895 AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Tong, Xishuai AU - Tong X AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Ran, Di AU - Ran D AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Ma, Yonggang AU - Ma Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. FAU - Liu, Zongping AU - Liu Z AUID- ORCID: 0000-0001-9071-8363 AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China. LA - eng GR - 32102732/National Natural Science Foundation of China/ GR - 31872533/National Natural Science Foundation of China/ GR - 32072933/National Natural Science Foundation of China/ GR - BK20210806/Natural Science Foundation of Jiangsu Province/ GR - 111 Project D18007/ GR - A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions（PAPD）/ PT - Journal Article DEP - 20230506 PL - United States TA - Environ Toxicol JT - Environmental toxicology JID - 100885357 RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - 00BH33GNGH (Cadmium) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Mice MH - *Proto-Oncogene Proteins c-akt/metabolism MH - Phosphatidylinositol 3-Kinase/metabolism MH - Cadmium/toxicity MH - Phosphatidylinositol 3-Kinases/metabolism MH - Osteocytes/metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/metabolism MH - Autophagy MH - Sirolimus/pharmacology MH - *Osteoporosis MH - Mammals/metabolism OTO - NOTNLM OT - autophagy OT - bone OT - cadmium OT - mice OT - osteocyte EDAT- 2023/05/06 09:42 MHDA- 2023/07/06 06:42 CRDT- 2023/05/06 05:43 PHST- 2023/04/18 00:00 [revised] PHST- 2023/02/12 00:00 [received] PHST- 2023/04/22 00:00 [accepted] PHST- 2023/07/06 06:42 [medline] PHST- 2023/05/06 09:42 [pubmed] PHST- 2023/05/06 05:43 [entrez] AID - 10.1002/tox.23823 [doi] PST - ppublish SO - Environ Toxicol. 2023 Aug;38(8):1980-1988. doi: 10.1002/tox.23823. Epub 2023 May 6.