AbstractThe epidermal growth factor receptor (EGFR) functions in various cellular physiological processes such as proliferation, differentiation, and motility. Although recent studies have reported that EGFR signaling is involved in osteoclast recruitment and formation, the molecular mechanism of EGFR signaling for the regulation of osteoclastogenesis remains unclear. We investigated the role of the EGFR in osteoclast differentiation and survival and show that the expression of the EGFR was highly up‐regulated by receptor activator of nuclear factor‐κB ligand (RANKL) during osteoclast differentiation. EGFR‐specific tyrosine kinase inhibitors and EGFR knockdown blocked RANKL‐dependent osteoclast formation, suggesting that EGFR signaling plays an important role in osteoclastogenesis. EGFR inhibition impaired the RANKL‐mediated activation of osteoclastogenic signaling pathways, including c‐Jun N‐terminal kinase (JNK), NF‐κB, and Akt/protein kinase B (PKB). In addition, EGFR inhibition in differentiated osteoclasts caused apoptosis through caspase activation. Inhibition of the phosphoinositide‐3 kinase (PI3K)‐Akt/PKB pathway and subsequent activation of BAD and caspases‐9 and ‐3 may be responsible for the EGFR inhibition‐induced apoptosis. The EGFR physically associated with receptor activator of nuclear factor‐κB (RANK) and Grb2‐associated binder 2 (Gab2). Moreover, RANKL transactivated EGFR. These data indicate that EGFR regulates RANKL‐activated signaling pathways by cross‐talking with RANK, suggesting that the EGFR may play a crucial role as a RANK downstream signal and/or a novel type of RANK co‐receptor in osteoclast differentiation and survival. J. Cell. Physiol. 217: 409–422, 2008. © 2008 Wiley‐Liss, Inc.