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Figure 5. Activation of the receptor RANK starts with trimerization of the receptor and subsequent binding of different tumor necrosis factor receptor-associated factors (TRAFs), including the most important, TRAF6, to the cytoplasmic tail of RANK. This leads to activation of the inhibitor-
B kinase (IKK) complex and subsequent phosphorylation of the nuclear factor-B (NF-B) inhibitor IB
, which then becomes ubiquitinated and degraded in proteasomes. Released NF-B dimers translocate to the nucleus and bind to responsive elements in different genes. The activation of NF-B can be inhibited by estrogen by mechanisms the details of which are unknown. Activation of RANK also leads to activation of the mitogen-activated protein kinases (MAP kinases) p38, extracellular signal-regulated kinases (ERK) 
, and c-jun amino-terminal kinase (JNK), which then phosphorylate and activate the transcription factor AP-1. Activation of ERK and JNK has also been shown to be inhibited by estrogen. In addition to RANK activation, stimulation of either FcR
or DAP12 is crucial for osteoclast differentiation. This pathway then leads to enhanced intracellular calcium and activation of calcineurin, which then dephosphorylates the transcription factor nuclear factor of activated T-cells 2 (NFAT2). It is not yet known if estrogen also affects this pathway. The importance of these pathways for osteoclastogenesis is shown by the findings that NF-B–/–, c-fos–/–, and NFAT2–/– mice all lack osteoclasts and are osteopetrotic.
