In the presence of lanthanum (La), the balance between osteogenesis and adipogenesis was broken in mouse mesenchymal stem cells (MSCs) in vitro, resulting in osteogenic induction and adipogenic inhibition, which were verified by alkaline phosphatase (ALP) activity and calcium secretion, and oil red O staining assays, respectively. The molecular data revealed that La up-regulated the expression levels of osteogenesis-associated genes and proteins, while it inhibited the expression of adipogenesis-associated genes and proteins. Furthermore, the mechanism of La on bone metabolism was investigated by screening 84 genes involved in differentiation of MSCs. The results showed that Smad1/5/8, a key protein involved in the bone morphogenetic protein (BMP) signaling pathway, was significantly phosphorylated under the exposure of La, leading to the activation of the BMP signaling pathway with subsequent up-regulation of the osteogenic genes and the down-regulation of the adipogenic genes.