YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulation in fetal bone development

Fetal bone development occurs by endochondral conversion of avascular cartilage to vascularized bone at the growth plate. This requires coordinated mobilization of osteoblast precursors with blood vessels. In adult bone, vessel-adjacent osteoblast precursors are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Here, we unify osteoblast precursor co-mobilization and mechanotransduction in a single signaling pathway, via the mechanosensitive transcriptional regulators YAP and TAZ. We show that YAP and TAZ spatially couple osteoblast precursor mobilization to angiogenesis, regulate vascular loop morphogenesis to control growth plate remodeling, and mediate mechanoregulation of load-induced osteogenesis in embryonic bone. Mechanistically, YAP and TAZ uniquely regulate a subset of osteoblast-lineage cells, identified by single-cell RNA sequencing as vessel-associated osteoblast precursors. Among these cells, YAP and TAZ regulate expression of the angiogenic chemokine, Cxcl12. Functionally, in 3D human cell co-culture, CXCL12 treatment rescued angiogenesis impaired by stromal cell YAP/TAZ depletion. Together, these data establish new functions of the vessel-associated osteoblast precursors in endochondral bone development. Overall design: Fetal forelimbs were generated from E17.5 mice from 3 genotypes - 2 control and 1 experimental. 1) YAPfl/fl; TAZfl/fl - hereafter WT(fl/fl) (n = 4 embryos), 2).YAPWT/WT; TAZWT/WT; Osx-cre - hereafter WT(Osx-cre) (n=4 embryos), 3) YAPfl/fl; TAZfl/fl; Osx-Cre - hereafter YAP/TAZ Osx cKO (n=3 embryos)