The YAP/TAZ transcriptional co-activators have opposing effects at different stages of osteoblast differentiation

Abstract

The related transcriptional co-factors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) have been proposed to either promote or inhibit osteoblast differentiation. Here we investigated the skeletal consequences of deleting YAP and TAZ at different stages of the osteoblast lineage using Prx1-Cre, Osx1-Cre, and Dmp1-Cre transgenic mice. Prx1-Cre-mediated deletion resulted in embryonic lethality. Mice lacking both copies of TAZ and one copy of YAP in cells targeted by Prx1-Cre were viable and displayed elevated bone mass associated increased bone formation. Deletion of YAP and TAZ using Osx1-Cre mice led to perinatal lethality. Suppression of Osx1-Cre activity until 21 days of age permitted postnatal deletion of YAP and TAZ, which resulted in increased osteoblast number at 12 weeks of age but no change in bone mass. Mechanistic studies revealed that YAP and TAZ suppress canonical Wnt signaling and Runx2 activity in osteoblast progenitors. Consistent with this, deletion of YAP and TAZ from osteoprogenitor cells increased osteoblast differentiation in vitro. Deletion of YAP and TAZ from mature osteoblasts and osteocytes using Dmp1-Cre mice led to reduced osteoblast number and bone formation, as well as increased osteoclast number, but no changes in known regulators of bone turnover such as RANKL, OPG, and Sost. Together these results suggest that YAP and TAZ in osteoblast progenitors oppose differentiation towards the osteoblast lineage but in mature osteoblasts and osteocytes, they promote bone formation and inhibit bone resorption.

Keywords: Osteoblast; Osteocyte; Transcriptional co-activator with PDZ-binding motif (TAZ); Wnt signaling; Yes-associated protein (YAP).