Objective To systemically investigate receptor activator of nuclear factor -κB ligand(RANKL) and macrophage colony-stimulating factor(M-CSF) induced differentiation of osteoclasts. Methods Mouse protein-protein interaction(PPI) database NIA and published microarray dataset GES16749 were used to construct and analyze PPI network of RANKL and M-CSF induced mouse monocyte RAW264.7. Results In the PPI network, transforming growth factor beta receptor 1(TGFBR1), Rous sarcoma oncogene(SRC), myelocytomatosis oncogene(MYC) and integrin beta 3(ITGB3) were able to interact with more proteins and they were the key nodes in the signaling transduction. Conclusion TGFBR1, SRC, MYC and ITGB3 might be the key points of RANKL and M-CSF induced differentiation of osteoclasts.