Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
Toxicol Sci. 2021 Jan 6;179(1):135-146. doi: 10.1093/toxsci/kfaa165.
Tungsten is a naturally occurring metal that is increasingly used in industry and medical devices, and is labeled as an emerging environmental contaminant. Like many metals, tungsten accumulates in bone. Our previous data indicate that tungsten decreases differentiation of osteoblasts, bone-forming cells. Herein, we explored the impact of tungsten on osteoclast differentiation, which function in bone resorption. We observed significantly elevated osteoclast numbers in the trabecular bone of femurs following oral exposure to tungsten in male, but not female mice. In order to explore the mechanism(s) by which tungsten increases osteoclast number, we utilized in vitro murine primary and cell line pre-osteoclast models. Although tungsten did not alter the adhesion of osteoclasts to the extracellular matrix protein, vitronectin, we did observe that tungsten enhanced RANKL-induced differentiation into tartrate-resistant acid phosphatase (TRAP)-positive mononucleated osteoclasts. Importantly, tungsten alone had no effect on differentiation or on the number of multinucleated TRAP-positive osteoclasts. Enhanced RANKL-induced differentiation correlated with increased gene expression of differentiated osteoclast markers Nfatc1, Acp5, and Ctsk. Although tungsten did not alter the RANK surface receptor expression, it did modulate its downstream signaling. Co-exposure of tungsten and RANKL resulted in sustained positive p38 signaling. These findings demonstrate that tungsten enhances sex-specific osteoclast differentiation, and together with previous findings of decreased osteoblastogenesis, implicate tungsten as a modulator of bone homeostasis.
钨是一种天然存在的金属，在工业和医疗器械中越来越多地被使用，并被标记为一种新兴的环境污染物。像许多金属一样，钨在骨骼中积累。我们之前的数据表明，钨会减少成骨细胞的分化，成骨细胞是形成骨骼的细胞。在此，我们探讨了钨对破骨细胞分化的影响，破骨细胞在骨骼吸收中发挥作用。我们观察到，雄性而非雌性小鼠经口服暴露于钨后，其股骨小梁骨中的破骨细胞数量显著增加。为了探讨钨增加破骨细胞数量的机制，我们利用了体外小鼠原代和细胞系前破骨细胞模型。尽管钨并未改变破骨细胞对细胞外基质蛋白 vitronectin 的黏附，但我们观察到钨增强了 RANKL 诱导的向抗酒石酸酸性磷酸酶（TRAP）阳性单核破骨细胞的分化。重要的是，钨本身对分化或多核 TRAP 阳性破骨细胞的数量没有影响。增强的 RANKL 诱导的分化与分化的破骨细胞标志物 Nfatc1、Acp5 和 Ctsk 的基因表达增加相关。尽管钨并未改变 RANK 表面受体的表达，但它调节了其下游信号转导。钨和 RANKL 的共同暴露导致持续的 p38 信号阳性。这些发现表明，钨增强了性别特异性的破骨细胞分化，与之前发现的成骨细胞生成减少一起，表明钨是骨稳态的调节剂。
