Mechanical stress plays an essential role in bone homeostasis by regulationg both bone formation and resorption. We have previously shown that cyclic stretch loading to MC3T3-E1 cells induced the expression of two bone remodeling related genes, Fn14 and MCP-3, through activation of ASK1 (a MAPKKK)/JNK and ASK1/p38 pathways, respectively. Here we show that cyclic stretch loading also induced the activation of TAK1 (another MAPKKK). Using TAK1 specific inhibitor 5Z-7 oxozeaenol, we revealed that TAK1 was required for the activation of at least four downstream pathways, namely, JNK, p38, NF-κB and NLK pathways. Moreover, TAK1 is activated via Ca2+-CaMKII pathway, resembling the non-canonical Wnt signaling pathway. These observations raise the possibility that TAK1 also plays various essential roles in mechanical stess-induced bone remodeling by activating diverse downstream pathways.