Low levels of cadmium exposure affect bone by inhibiting Lgr4 expression in osteoblasts and osteoclasts.

BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS:Our data indicates that cadmium may induce bone loss by inhibiting Lgr4-related bone formation and promoting Lgr4-related osteoclast formation.