YAP1 is essential for osteoclastogenesis through a TEADs-dependent mechanism

Area of Science:

• Cell Biology
• Molecular Biology
• Skeletal Biology

Background:

• Yes-associated protein 1 (YAP1) is a key effector of the Hippo signaling pathway, regulating cell proliferation and differentiation.
• YAP1 influences skeletal development and bone remodeling, including mesenchymal stem cell (MSC) behavior.
• The specific role of YAP1 in osteoclastogenesis, the process of forming osteoclasts, was previously unclear.

Purpose of the Study:

• To investigate the role of YAP1 in osteoclast differentiation and function.
• To elucidate the molecular mechanisms by which YAP1 regulates osteoclastogenesis.

Main Methods:

• Studied YAP1 expression during RANKL-induced osteoclastogenesis.
• Utilized short hairpin RNA (shRNA) to knock down YAP1 in bone marrow-derived macrophages (BMM).
• Administered verteporfin, a YAP1/TEAD inhibitor, to BMM and assessed osteoclastogenesis and bone resorption.

Main Results:

• YAP1 mRNA and protein levels decreased during osteoclastogenesis.
• YAP1 knockdown in BMM inhibited multinucleated osteoclast formation, function, and marker gene expression.
• Verteporfin treatment suppressed osteoclastogenesis and bone resorption activity.
• Confirmed YAP1/TEAD interaction with AP-1 for gene transcription and observed impaired RANKL-induced NF-κB signaling upon YAP1 inhibition.

Conclusions:

• YAP1 is an essential regulator of osteoclast differentiation and activity.
• The YAP1/TEAD complex plays a critical role in controlling osteoclastogenesis and associated gene expression.
• YAP1 inhibition impacts key signaling pathways like NF-κB, affecting osteoclast function.