Abstract
Osteogenesis is categorized into two groups based on developmental histology, intramembranous and endochondral ossification. The role of blood vessels during endochondral ossification is well known, while their role in intramembranous ossification, especially the intertissue pathway, is poorly understood. Here, we demonstrate endothelial Yap/Taz is a novel regulator of intramembranous ossification in zebrafish. Appropriate blood flow is required for Yap/Taz transcriptional activation in endothelial cells and intramembranous ossification. Additionally, Yap/Taz transcriptional activity in endothelial cells specifically promotes intramembranous ossification. BMP expression by Yap/Taz transactivation in endothelial cells is also identified as a bridging factor between blood vessels and intramembranous ossification. Furthermore, the expression of Runx2 in pre-osteoblast cells is a downstream target of Yap/Taz transcriptional activity in endothelial cells. Our results provide novel insight into the relationship between blood flow and ossification by demonstrating intertissue regulation.
Highlights
The role of Yap/Taz transactivation in promoting osteogenesis has been studied previously[16,17,18]
To confirm that the truncated hTead2ΔN or hYapN inhibit Yap/Taz transcriptional activity, we measured the transcriptional activity of Yap/Taz based on the Gal4/UAS system (Fig. 1a and Supplemental Fig. S1)23. 293T cells were transfected with pFR-Luc and pcDNA3.1-Gal4-hTead2ΔN for measuring the transcriptional activities of zYap or zTaz cells
We demonstrated the intertissue relationship between blood flow and osteogenesis in zebrafish
Summary
The role of Yap/Taz transactivation in promoting osteogenesis has been studied previously[16,17,18]. Osteogenesis remained intact despite systematic depletion of Taz in mice[19,20,21] though a similar depletion of Taz abolished bone formation in Zebrafish[18]. Most studies have shown the requirement of Yap/Taz in mesenchymal stem cells and osteoblast cells during osteogenesis in vitro, the role of Yap/Taz in vivo osteogenesis is unclear. Yap/Taz transcriptional activity in endothelial cells promotes intramembranous ossification via Runx[2] expression. We identified BMP4 as a bridging factor between endothelial cells and osteoblast cells. These results highlight the intertissue pathway during osteogenesis
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