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Low-dose cadmium exposure acts on rat mesenchymal stem cells via RANKL/OPG and downregulate osteogenic differentiation genes

Lv, Ying-Jian, Wei, Qin-Zhi, Zhang, Yang-Cong, Huang, Rui, Li, Bai-Sheng, Tan, Jian-Bin, Wang, Jing, Ling, Hai-Tuan, Wu, Shi-Xuan, Yang, Xing-Fen
Environmental pollution 2019 v.249 pp. 620-628
albumins, autophagy, body weight, bone formation, cadmium, cadmium chloride, calcium, collagen, excretion, gene expression, gene expression regulation, genes, heme oxygenase (biliverdin-producing), histology, ligands, mesenchymal stromal cells, molecular weight, nephrotoxicity, osteopontin, rats, stress response, transcription factor NF-kappa B
Chronic cadmium (Cd) toxicity is a significant health concern, and the mechanism of long-term low-dose Cd exposure on bone has not been fully elucidated till date. This study aimed to assess the association between rat mesenchymal stem cells (MSCs) and long-term Cd exposure through 38-week intake of CdCl2 at 1 and 2 mg/kg body weight (bw). Increased gene expression of receptor activator of NF-κB ligand (RANKL) and decreased gene expression of osteoprotegerin (OPG) were observed. Fold change of RANKL gene expression (fold change = 1.97) and OPG gene expression (fold change = 1.72) showed statistically significant differences at dose 2 mg/kg bw. Decreased expression of key genes was observed during the early osteogenic differentiation of MSCs. The gene expression of Osterix in 1 mg/kg bw group was decreased by 3.70-fold, and the gene expressions of Osterix, Osteopontin, collagen type I alpha 2 chain (COL1a2) and runt-related transcription factor 2 (RUNX2) in 2 mg/kg bw group were decreased by 1.79, 1.67, 1.45 and 1.35-folds, respectively. Exposure to CdCl2 induced an increase in the renal Cd load, but only an adaptive response was observed, including increased expression of autophagy-related proteins LC3B and Beclin-1, autophagy receptor p62, and heme oxygenase 1 (HO-1), which is an inducible isoform that releases in response to stress. There were no significant changes in the urinary low molecular weight proteins including N-acetyl-b-D-glucosaminidase (NAG), β2-microglobulin and albumin (U-Alb). Urinary calcium (Ca) excretion showed no increase, and no obvious renal histological changes. Taken together, these results indicated that the chronic CdCl2 exposure directly act on MSCs through RANKL/OPG pathway and downregulate the key genes involved in osteogenic differentiation of MSCs. The toxic effect of Cd on bone may occur in parallel to nephrotoxicity.