TNF-${alpha}$, a proinflammatory cytokine, inhibits osteoblast differentiation under diverse inflammatory conditions; however, the underlying mechanisms in terms of the TNF-${alpha}$ signaling pathway remain unclear. In this study, we examined the role of Msx2 in TNF-${alpha}$-mediated inhibition of alkaline phosphatase (ALP) expression and the signaling pathways involved. TNF-${alpha}$ down-regulated ALP expression induced by bone morphogenetic protein 2 (BMP2) in C2C12 and Runx2$^{-/-}$ calvarial cells. Over-expression of Msx2 suppressed BMP2-induced ALP expression. Furthermore, TNF-${alpha}$ induced Msx2 expression, and the knockdown of Msx2 by small interfering RNAs rescued ALP expression, which was inhibited by TNF-${alpha}$. TNF-${alpha}$ activated the NF-${kappa}$B and the JNK pathways. Inhibition of NF-${kappa}$B or JNK activation reduced the inhibitory effect of TNF-${alpha}$ on ALP expression, whereas TNF-${alpha}$-induced Msx2 expression was only suppressed by the inhibition of the NF-${kappa}$B pathway. Taken together, these results indicate that Msx2 mediates the inhibitory action of TNF-${alpha}$ on BMP2-regulated osteoblast differentiation and that the TNF-${alpha}$-activated NF-${kappa}$B pathway is responsible for Msx2 induction.