MircoRNA-143-3p regulating ARL6 is involved in the cadmium-induced inhibition of osteogenic differentiation in human bone marrow mesenchymal stem cells.

Cadmium, which is extensively distributed in the environment, accumulates in organisms through the trophic chain. Although cadmium can cause bone injury, its role in osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) remains unclear. The present study investigated the effect of cadmium chloride (CdCl2) on osteogenesis of hBMSCs and the underlying mechanism. CdCl2 dose-dependently reduced the viability of hBMSCs. Concentrations of CdCl2 (2.5 and 5.0 µM) increased miR-143-3p levels; decreased levels of adenosine diphosphate-ribosylation factor-like protein 6 (ARL6); inhibited Wnt family member 3A (Wnt3a), ß-catenin, lymphoid enhancer factor (LEF1), and T-cell factor 1 (TCF1); and suppressed osteogenesis of hBMSCs. Inhibition of miR-143-3p or overexpression of ARL6 with lentivirus blocked these CdCl2-induced changes. Luciferase reporter assays confirmed that miR-143-3p binds to the 3'-UTR regions of ARL6 mRNA. Reduced-expression of miR-143-3p enhanced the CdCl2-induced suppression of the osteogenesis of hBMSCs and inhibition of the Wnt/ß-catenin pathway, effects that were reversed by down-regulated expression of ARL6. Thus, miR-143-3p targets ARL6 to down-regulate the Wnt/ß-catenin pathway, which is involved in the suppression of osteogenic differentiation of hBMSCs. The results provide new directions for clinical treatment of bone diseases resulting from cadmium toxicity.

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

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), ß2-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.