Yes-associated protein 1 (YAP1), the core effector of the Hippo signaling pathway, has been identified as a key regulator of tissue homeostasis and organ development by controlling cell proliferation and differentiation. Previous studies have shown that YAPI regulates multiple steps during skeletal development and bone remodeling, including the self-renewal and differentiation of mesenchymal stem cells (MSCs). However, its role in osteoclastogenesis remains largely unknown. Here, we report that YAPI is an essential regulator for osteoclast differentiation and activity. Both mRNA and protein levels of YAPI were downregulated during RANKL-induced osteoclastogenesis. Short hairpin RNA-mediated knockdown of YAPI in bone marrow-derived macrophages (BMM) prevented the formation and function of multinucleated osteoclasts, and markedly abrogated the expression of osteoclast marker genes. Furthermore, the suppression of osteoclastogenesis and bone resorption activity were also observed in the BMM treated with verteporfin, a small molecule that inhibits the association of YAPI with the transcriptional enhancer-associated domain (TEAD) family of transcription factors, the major partner of YAP1. Mechanistically, the interaction of YAPI/FEADs with AP-1 and cooperation on downstream gene transcription were confirmed, and RANKL-induced NF-kappa B signaling was also impaired in the YAP1-inhibited condition. Our results revealed the essential role of YAPI and the YAP1-TEADs complex in regulating osteoclastogenesis and related gene expression. (C) 2018 Published by Elsevier Inc.