Bone morphogenetic protein 4 is involved in cadmium-associated bone damage.

Cadmium is a well-characterized bone toxic agent and can induce bone damage via inhibiting osteogenic differentiation. BMP/SMAD signaling pathway can mediate osteogenic differentiation, but the association between cadmium and BMP/SMAD signaling pathway is yet to be illuminated. To understand what elements of BMPs and SMADs are affected by Cd to influence osteogenic differentiation and if BMPs can be the biomarkers of which Cd-induced osteoporosis, human bone marrow mesenchymal stem cells were treated with CdCl2 in vitro to detect the expression of BMPs and SMADs, and 134 subjects were enrolled to explore if the BMPs can be potential biomarkers of cadmium-associated bone damage. Our results show that Cd exposure significantly promoted the adipogenic differentiation of hBMSCs and inhibited its osteogenic differentiation by inhibiting the expression of BMP-2/4, SMAD4, and p-SMAD1/5/9 complex. And mediation analyses yielded that BMP-4 mediated 39.32% (95%CI 7.47, 85.00) of the total association between the cadmium and the risk of cadmium-associated bone damage. Moreover, during differentiation, BMP-4 had the potential to enhance mineralization compared to CdCl2 only group. These results reveal that BMP-4 can be a diagnostic biomarker and therapeutic target for cadmium-associated bone damage.