Aim To evaluate the impact of previously unrecognized negative interaction between the Wnt and interleukin (IL) 6 signaling pathways in skeletal tissues as a possible major mechanism leading to age- and inflammation-related destruction of bone and joints. Methods Luciferase reporter assays were performed to monitor Wnt pathway activation upon IL-6 and tumor necrosis factor-α (TNFα) treatment. Functional contribution of IL-6 and TNFα interaction to inhibition of bone formation was evaluated in vitro using small hairpin RNAs (shRNA) in mouse mesenchymal precursor cells (MPC) of C2C12 and KS483 lines induced to differentiate into osteoblasts by bone morphogenetic proteins (BMP). Results IL-6 inhibited the activation of Wnt signaling in primary human synoviocytes, and, together with TNFα and Dickkopf-1, inhibited the activation of Wnt response. ShRNA-mediated knockdown of IL-6 mRNA significantly increased early BMP2/7-induced osteogenesis and rescued it from the negative effect of TNFα in C2C12 cells, as well as intensified bone matrix mineralization in KS483 cells. Conclusion IL-6 is an important mediator in the inhibition of osteoblast differentiation by TNFα, and knockdown of IL-6 partially rescues osteogenesis from the negative control of inflammation. The anti-osteoblastic effects of IL-6 are most likely mediated by its negative interaction with Wnt signaling pathway