YAP1 is essential for osteoclastogenesis through a TEADs-dependent mechanism.
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 YAP1 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 YAP1 is an essential regulator for osteoclast differentiation and activity. Both mRNA and protein levels of YAP1 were downregulated during RANKL-induced osteoclastogenesis. Short hairpin RNA-mediated knockdown of YAP1 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 YAP1 with the transcriptional enhancer-associated domain (TEAD) family of transcription factors, the major partner of YAP1. Mechanistically, the interaction of YAP1/TEADs with AP-1 and cooperation on downstream gene transcription were confirmed, and RANKL-induced NF-κB signaling was also impaired in the YAP1-inhibited condition. Our results revealed the essential role of YAP1 and the YAP1-TEADs complex in regulating osteoclastogenesis and related gene expression.
['Zhao|Liming|L|', 'Guan|Hanfeng|H|', 'Song|Chao|C|', 'Wang|Yuting|Y|', 'Liu|Changyu|C|', 'Cai|Cong|C|', 'Zhu|Hao|H|', 'Liu|Hui|H|', 'Zhao|Libo|L|', 'Xiao|Jun|J|']
D048868:Adaptor Proteins, Signal Transducing D000256:Adenoviridae D000818:Animals D018797:Cell Cycle Proteins D002454:Cell Differentiation D049109:Cell Proliferation D003470:Culture Media D004268:DNA-Binding Proteins D020869:Gene Expression Profiling D005786:Gene Expression Regulation D018507:Gene Expression Regulation, Developmental D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009124:Muscle Proteins D052002:NF-kappa B p50 Subunit D010010:Osteoclasts D010012:Osteogenesis D010750:Phosphoproteins D010766:Phosphorylation D010957:Plasmids D015398:Signal Transduction D000091262:TEA Domain Transcription Factors D018808:Transcription Factor AP-1 D014157:Transcription Factors D000077362:Verteporfin D000091102:YAP-Signaling Proteins
YAP1 Osteoclast TEADs AP-1 NF-κB