YAP regulates transcriptional programs for layer-specific periosteal expansion during fracture repair
- Madhura P. Nijsure
- Brendan Tobin
- Dakota L. Jones
- Annemarie Lang
- Grey Hallström
- Miriam Baitner
- Gabrielle I. Tanner
- Georgios Kotsaris
- Yasaman Moharrer
- Christopher J. Panebianco
- Elizabeth G. Seidl
- Nathaniel A. Dyment
- Gregory L. Szeto
- Levi Wood
- Joel D. Boerckel
2025-08-06
Bone fracture repair initiates by periosteal expansion. The periosteum is a bilayered tissue composed of inner cambium and outer fibrous layers. Typically quiescent, periosteal progenitor cells proliferate upon fracture; however, the underlying transcriptional mechanisms remain unclear. Here, we show that deletion of the transcriptional regulators, yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), from Osterix-expressing cells, which reside in the cambium, impairs periosteal expansion. YAP activation increases chromatin accessibility, preferentially at TEA domain transcription factor (TEAD) binding sites, and regulates both cell-intrinsic and cell-extrinsic cellular functions. We identify bone morphogenetic protein 4 ( Bmp4 ) as a YAP-TEAD target gene expressed in the cambium. In YAP/TAZ knockout mice, BMP4 delivery increased periosteal expansion through matrix accumulation and fibrous layer cell proliferation. Conversely, in wild-type mice, BMP4 delivery increased osteogenic activity and angiogenesis. Together, these data identify YAP-mediated transcriptional programs that promote layer-specific periosteal expansion.