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Arsenic induces human chondrocyte senescence and accelerates rat articular cartilage aging

  • Inorganic Compounds
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Abstract

Arsenic-contaminated drinking water is known to be a serious human health problem. A previous epidemiological study has indicated that arsenic levels in blood were higher in arthritis patients compared to age-matched control subjects. Bone is known as an important arsenic store compartment in the body. Arsenic exposure has been suggested to promote senescence in human mesenchymal stem cells that may affect the balance of adipogenic and osteogenic differentiation. The toxicological effect and mechanism of arsenic exposure on articular chondrocytes still remain unclear. Here, we investigated the arsenic-induced senescence in cultured human articular chondrocytes and long-term arsenic-exposed rat articular cartilage. Arsenic trioxide (As2O3; 1–5 μM) significantly induced senescence in human articular chondrocytes by increasing senescence-associated β-galactosidase (SA-β-Gal) activity and protein expression of p16, p53, and p21. Arsenic induced the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) proteins. The inhibitors of p38 and JNK significantly reversed the arsenic-induced chondrocyte senescence. Arsenic could also trigger the induction of GATA4-NF-κB signaling and senescence-associated secretory phenotype (SASP) by increasing IL-1α, IL-1β, TGF-β, TNF-α, CCL2, PAI-1, and MMP13 mRNA expression. The increased cartilage senescence and abrasion were also observed in a rat model long-term treatment with arsenic (0.05 and 0.5 ppm) in drinking water for 36 weeks as compared to age-matched control rats. The phosphorylation of p38 and JNK and the induction of GATA4-NF-κB signaling and SASP were enhanced in the rat cartilages. Taken together, these findings suggest that arsenic exposure is capable of inducing chondrocyte senescence and accelerating rat articular cartilage aging and abrasion.

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Acknowledgements

This study was funded by grants from Ministry of Science and Technology of Taiwan (NSC101-2314-B-002-118-MY2; MOST105-2314-B-002-009-MY3).

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  1. Yao-Pang Chung and Ya-Wen Chen contributed equally to this study.

Authors and Affiliations

  1. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Yao-Pang Chung & Shing-Hwa Liu

  2. Department of Physiology and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan

    Ya-Wen Chen

  3. Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    Te-I Weng

  4. Departments of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan

    Rong-Sen Yang

  5. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan

    Shing-Hwa Liu

  6. Department of Pediatrics, College of Medicine, National Taiwan University and Hospital, Taipei, Taiwan

    Shing-Hwa Liu

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  1. Yao-Pang Chung
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Correspondence to Rong-Sen Yang or Shing-Hwa Liu.

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Chung, YP., Chen, YW., Weng, TI. et al. Arsenic induces human chondrocyte senescence and accelerates rat articular cartilage aging. Arch Toxicol 94, 89–101 (2020). https://doi.org/10.1007/s00204-019-02607-2

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