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.

中文翻译：

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砷诱导人软骨细胞衰老并加速大鼠关节软骨的衰老。

众所周知，砷污染的饮用水是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，关节炎患者的血液中砷含量更高。骨骼被称为体内重要的砷储存室。已建议砷暴露促进人间充质干细胞的衰老，这可能会影响成脂和成骨分化的平衡。砷对关节软骨细胞的毒理作用和机理尚不清楚。在这里，我们调查了培养的人关节软骨细胞和长期暴露于砷的大鼠关节软骨中砷诱导的衰老。三氧化二砷（As2O3; 1-5μM）通过增加衰老相关的β-半乳糖苷酶（SA-β-Gal）活性和p16，p53和p21的蛋白表达来显着诱导人关节软骨细胞的衰老。砷诱导p38和c-Jun N末端激酶（JNK）蛋白磷酸化。p38和JNK的抑制剂可显着逆转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表达来诱导GATA4-NF-κB信号传导和衰老相关的分泌表型（SASP）的诱导。 。与年龄相匹配的对照组大鼠相比，在长期用饮用水中砷（0.05和0.5 ppm）处理36周的大鼠模型中，还观察到了软骨衰老和磨损的增加。在大鼠软骨中，p38和JNK的磷酸化以及对GATA4-NF-κB信号传导和SASP的诱导增强。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的衰老和磨损。