2. Academic Validation
  3. P62 acts as an intermediator in cadmium-induced osteocyte apoptosis and osteoporosis in mice

P62 acts as an intermediator in cadmium-induced osteocyte apoptosis and osteoporosis in mice

  • Biochem Pharmacol. 2025 Oct:240:117104. doi: 10.1016/j.bcp.2025.117104.
Fan Yu 1,  Linping Liu 1,  Waseem Ali 1,  Yonggang Ma 1,  Ruilong Song 1,  Hongyan Zhao 1,  Hui Zou 1,  Jianchun Bian 1,  Yan Yuan 1,  Jianhong Gu 1,  Xishuai Tong 2,  Zongping Liu 3
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Institute of Agricultural Science and Technology Development, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China.
  • 2 College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Institute of Agricultural Science and Technology Development, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China. Electronic address: xstong@yzu.edu.cn.
  • 3 College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Institute of Agricultural Science and Technology Development, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China. Electronic address: liuzongping@yzu.edu.cn.
PMID: 40619031 DOI: 10.1016/j.bcp.2025.117104
Abstract

Cadmium (Cd) is a pervasive environmental pollutant. The skeletal system is particularly susceptible and Cd exposure linked to the development of osteoporosis. Intracellular p62 is closely related to bone remodeling and bone marrow integrity. However, the mechanisms of p62 underlying Cd-induced osteocyte damage and osteoporosis remain inadequately understood. A Cd-induced bone injury model was established in C57BL/6 mice, along with a cellular damage model using murine long bone osteocyte-y4 (MLO-Y4) cells. Our study revealed Cd exposure led to p62 high protein levels, disrupting bone homeostasis and promoting osteoporosis in vivo. Further cellular experiments revealed that Cd-induced Autophagy dysregulation and lysosomal dysfunction resulted in p62 high protein levels, which triggered osteocyte Apoptosis. Autophagy modulation studies demonstrated that rapamycin (RAPA) reduced p62 levels, and alleviated Apoptosis, whereas chloroquine (CQ) exacerbated these effects. Importantly, p62 knockout or Apoptosis inhibition significantly reduced osteocyte Apoptosis and preserved bone homeostasis. In vivo, p62 deficiency effectively mitigated Cd-induced osteoporosis, highlighting its critical role in the pathogenesis of Cd-induced skeletal damage. This study identifies p62 as a central mediator of Cd-induced osteocyte damage and osteoporosis, providing valuable insights into its molecular mechanisms. Targeting p62 may represent a novel therapeutic strategy for preventing or treating Cd-associated bone disorders.

Keywords

Apoptosis; Cadmium (Cd); Osteocyte; Osteoporosis; P62.

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