Wnt/β-Catenin Pathway Is Involved in Cadmium-Induced Inhibition of Osteoblast Differentiation of Bone Marrow Mesenchymal Stem Cells

Abstract

Cadmium is a common environmental pollutant that causes bone damage. However, the effects of cadmium on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) and its mechanism of action in this process are unclear. Here, we determined the effects of cadmium chloride (CdCl2) on the osteogenic differentiation of BMMSCs and the potential mechanism involved in this process. As determined in the present investigation, CdCl2, in a concentration-dependent manner, affected the viability of BMMSCs and their cytoskeletons. Exposure to 0.1 or 0.2 µM CdCl2 inhibited osteogenic differentiation of BMMSCs, which was reflected in the down-regulation of osteoblast-related genes (ALP, OCN, Runx2, OSX, and OPN); in suppression of the protein expression of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2); and in decreased ALP activity and capacity for mineralization. Moreover, mRNA microarray was performed to determine the roles of these factors in BMMSCs treated with CdCl2 in comparison to control BMMSCs. As determined with the microarrays, the Wingless-type (Wnt), mothers against decapentaplegic and the C. elegans gene Sam (SMAD), and Janus kinase-Signal Transducers and Activators of Transcription (JAK-STAT) signaling pathways were involved in the effects caused by CdCl2. Moreover, during differentiation, the protein levels of Wnt3a, β-catenin, lymphoid enhancer factor 1 (LEF1), and T-cell factor 1 (TCF1) were reduced by CdCl2. The current research shows that CdCl2 suppresses the osteogenesis of BMMSCs via inhibiting the Wnt/β-catenin pathway. The results establish a previously unknown mechanism for bone injury induced by CdCl2.

FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells

“…All data are expressed as the mean ± standard deviation (SD). Statistical analyses were performed on SPSS software version 19.0 (IBM SPSS, Armonk, NY, USA). Statistical differences between groups were determined via one-way ANOVA, and Tukey's multiple comparisons test, with a significance level of p < .05.…”

“…Conversely, loss of BMP/Smad signaling pathways often leads to bone-related diseases, such as osteoporosis [18]. Wnt signal also promotes bone formation through b-catenin dependent or independent signal transduction [19]. Besides, MAPK signal pathway, including JNK, ERK and p38 pathways have been largely reported to promote bone formation in vitro and vivo [20,21].…”

Adverse Impact of Heavy Metals on Bone Cells and Bone Metabolism Dependently and Independently through Anemia

“…[73] Moreover, Cd inhibited osteogenic differentiation of bone marrow MSCs (BMMSCs) by downregulating osteoblast-related genes (RUNX2, OCN, OSX, and OPN) and suppressing alkaline phosphatase (ALP), via inhibition on the Wnt/ -catenin pathway, as demonstrated by the reduced protein levels of -catenin, Wnt3a lymphoid enhancer factor 1 (LEF1) and T-cell factor 1 (TCF1). [74] Additionally, Cd exposure induced osteoblast apoptosis by cytoskeleton disruption (via actin depolymerization), [75] DNA fragmentation (by inducing reactive oxygen species (ROS)) [76] and oxidative stress (by activating the p38 MAPK pathway and inhibiting the Erk1/2 pathway). [77] In the meanwhile, Cd promoted bone resorption, as indicated by the increased TRAP-positive osteoclasts.…”

“…Reduced ratio of OPG and RANKL via altered expression of IL-1, IL-17 and TGF- [72] Inhibited expression of RUNX2, OSX, OPN, OCN and COL1A2 by suppressing the Wnt/ -catenin pathway [ 72,74] Induction of osteoblast apoptosis Cytoskeleton disruption owing to actin depolymerization [75] DNA fragmentation probably by inducing ROS [76] Oxidative stress via activation of p38 MAPK pathway and inhibition of Erk1/2 pathway [77] Enhanced osteoclast differentiation Increased ratio of RANKL/OPG and TRAP activity [ 67,78] Increased levels of IL-6 and IL-8 in osteoblasts via TLR4 activation [78] Inhibited formation and enhanced degradation of extracellular bone matrix Induction of MMP1, MMP3, MMP9 and MMP13, and decreased synthesis of collagen 1, GAGs and PGs via inflammatory response (IL-1 and IL-6) and ROS production [ 78,81] Disturbed Ca and P homeostasis and inhibited mineralization…”

Cadmium Toxicity on Chondrocytes and the Palliative Effects of 1α, 25-Dihydroxy Vitamin D3 in White Leghorns Chicken's Embryo

“…Existing research on the Cd osteotoxicity at the cellular level is mostly focused on osteoclasts and osteoblasts ( 14 , 15 ). Cd induces apoptosis in osteoblasts through mitochondrial damage and oxidative stress, reduces the secretion of collagen and other components of bone matrix as well as alkaline phosphatase (ALP) activity, and inhibits the differentiation of rat osteoblast through the Wnt/beta-catenin signaling pathway ( 16 , 17 ). Low concentrations of Cd (7.5–60 nmol/L) also induce mice osteoclast differentiation and bone resorption through Ca 2+ /CaM/CaMK signaling ( 18 ).…”