Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
Institute of Radiation Medicine, Fudan University, 2094 Xietu road, Shanghai 200032, China.
J Trace Elem Med Biol. 2022 Sep;73:127025. doi: 10.1016/j.jtemb.2022.127025. Epub 2022 Jun 22.
Cadmium exposure is associated with bone loss. However, the mechanisms involved have not yet been fully understood. Leucine-rich repeat containing GPCR-4 (LGR4) can bind with the receptor activator of nuclear factors κB ligand (RANKL) and inhibit osteoclast formation. In addition, Lgr4 plays an important role in maintaining osteoblast activity. In the present study the effect of cadmium exposure on bone was investigated in terms of Lgr4 expression.
Raw 264.7 cells and primary osteoblasts were exposed to cadmium (0-60 nM/L). The effects of cadmium on osteoclast formation and osteoblast activity were investigated. Osteoclast differentiation-related (Traf6, NFATc1) and osteoblast-related (RANKL; osteoprotegerin, OPG) gene and protein expression were determined. Lgr4 expression in osteoclasts and osteoblasts were also determined. A rat model was established to show the effects of cadmium (50 mg/L) on bone loss and Lgr4 expression in vivo.
Cadmium exposure inhibited osteoblast activities and stimulated osteoclast formation. Cadmium exposure also inhibited Lgr4 expression in both osteoclasts and osteoblasts. Low dose of RANKL added to the culture medium could promote osteoclast formation in cadmium-pretreated RAW264.7 cells. Blocking Lgr4 in osteoclasts only slightly inhibited cadmium-induced osteoclast formation in cadmium-pretreated RAW264.7 cells. Cadmium significantly upregulated the AKT/ERK signaling pathway. An in vivo study showed that cadmium exposure promoted osteoclast formation and inhibited Lgr4 expression.
Our data indicates that cadmium may induce bone loss by inhibiting Lgr4-related bone formation and promoting Lgr4-related osteoclast formation.
镉暴露与骨丢失有关。然而，其涉及的机制尚未完全阐明。富含亮氨酸重复序列的 G 蛋白偶联受体 4（LGR4）可以与核因子κB 受体激活剂配体（RANKL）结合，并抑制破骨细胞的形成。此外，Lgr4 在维持成骨细胞活性方面发挥着重要作用。在本研究中，我们研究了镉暴露对 Lgr4 表达的影响，以探讨其对骨的作用。
将 Raw 264.7 细胞和原代成骨细胞暴露于镉（0-60 nM/L）中。研究了镉对破骨细胞形成和成骨细胞活性的影响。检测了破骨细胞分化相关（Traf6、NFATc1）和成骨细胞相关（RANKL；骨保护素，OPG）基因和蛋白的表达。还检测了破骨细胞和成骨细胞中 Lgr4 的表达。建立大鼠模型以显示体内镉（50 mg/L）对骨丢失和 Lgr4 表达的影响。
镉暴露抑制成骨细胞活性并刺激破骨细胞形成。镉暴露还抑制了破骨细胞和成骨细胞中 Lgr4 的表达。在预先用镉处理的 RAW264.7 细胞的培养基中添加低剂量的 RANKL 可以促进破骨细胞的形成。阻断破骨细胞中的 Lgr4 仅略微抑制了预先用镉处理的 RAW264.7 细胞中镉诱导的破骨细胞形成。镉显著上调 AKT/ERK 信号通路。体内研究表明，镉暴露促进破骨细胞形成并抑制 Lgr4 表达。
我们的数据表明，镉可能通过抑制 Lgr4 相关的骨形成和促进 Lgr4 相关的破骨细胞形成来诱导骨丢失。
