Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Physiology and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
Arch Toxicol. 2020 Jan;94(1):89-101. doi: 10.1007/s00204-019-02607-2. Epub 2019 Nov 16.
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 (AsO; 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.
饮用水中的砷污染已被证实是一个严重的人类健康问题。先前的一项流行病学研究表明，与年龄匹配的对照组相比，关节炎患者血液中的砷水平更高。骨骼被认为是体内重要的砷储存部位。有研究表明，砷暴露会促进人骨髓间充质干细胞衰老，从而可能影响成脂和成骨分化的平衡。砷暴露对关节软骨细胞的毒性作用和机制仍不清楚。在这里，我们研究了砷对培养的人关节软骨细胞和长期砷暴露的大鼠关节软骨的诱导衰老作用。三氧化二砷（As2O3；1-5μM）通过增加衰老相关β-半乳糖苷酶（SA-β-Gal）活性和 p16、p53 和 p21 的蛋白表达，显著诱导人关节软骨细胞衰老。砷诱导 p38 和 c-Jun N 端激酶（JNK）蛋白磷酸化。p38 和 JNK 的抑制剂显著逆转了砷诱导的软骨细胞衰老。砷还可以通过增加 IL-1α、IL-1β、TGF-β、TNF-α、CCL2、PAI-1 和 MMP13 mRNA 表达，触发 GATA4-NF-κB 信号和衰老相关分泌表型（SASP）的诱导。与年龄匹配的对照组大鼠相比，在饮用水中连续 36 周给予 0.05 和 0.5ppm 的砷（大鼠模型）进行长期治疗，也观察到大鼠软骨中软骨衰老和磨损增加。p38 和 JNK 的磷酸化以及 GATA4-NF-κB 信号和 SASP 的诱导在大鼠软骨中增强。综上所述，这些发现表明，砷暴露能够诱导软骨细胞衰老，并加速大鼠关节软骨老化和磨损。
