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. 2015 Aug 28;4(9):1741–1752. doi: 10.3390/jcm4091741

Figure 1.

Figure 1

An important signaling cascade of osteoclastogenesis. The binding of M-CSF to its receptor, c-Fms, induces the transcription factor c-Fos, whereas the binding of RANKL to its receptor, RANK, leads to the recruitment of TRAF6, the main adapter molecule of RANK. TRAF6 activates NF-κB and mitogen-activated kinases including JNK. JNK in turn activates the transcription factor c-Jun. RANKL/RANK also induces c-Fos to form AP-1, a heterodimeric transcription factor, with c-Jun. AP-1 and NF-κB then induce NFATc1, a master transcription factor that regulates osteoclast differentiation. NFATc1 works together with other transcription factors such as AP-1, PU.1, and MITF to induce various osteoclast-specific genes. Thus, M-CSF and RANKL signaling pathways are crucial for osteoclastogenesis. On the other hand, the RANK–RANKL interaction is inhibited by the decoy receptor OPG expressed by stromal cells and osteoblasts.