Endothelial PIEZO1 activation impairs osteogenesis via GREM1-mediated inhibition of BMP signaling [hBMEC_RNA-seq]

Here, we show that systemic activation of PIEZO1 using the chemical agonist Yoda1 in 3-week-old mice disrupts bone homeostasis by impairing type H endothelial cells and inhibiting osteogenic differentiation. In vivo, Yoda1 treatment significantly reduced the abundance of CD31hiEMCNhi type H vessels and altered trabecular bone microarchitecture without affecting total bone mass.

In vitro, Yoda1 inhibited osteogenic gene expression and alkaline phosphatase activity in MC3T3-E1 preosteoblasts. Transcriptomic analysis of Yoda1-treated human bone microvascular endothelial cells (hBMECs) revealed a shift from an angiogenic H-type to a quiescent L-type, accompanied by upregulation of BMP signaling antagonists, particularly GREM1. Functional assays confirmed that GREM1 secreted from Yoda1-stimulated endothelial cells suppresses BMP4-induced osteoblast differentiation via paracrine signaling.