Frizzled-9 activates YAP to rescue simulated microgravity induced osteoblasts dysfunction

Abstract Long-term space flight will lead to bone loss and osteoblasts dysfunction. The underlying mechanism is still far to reveal. Frizzled-9 (Fzd9) is a Wnt receptor which is essential to osteoblasts differentiation and bone formation. Here we investigate whether Fzd9 plays a role in simulated microgravity (SMG) induced osteoblasts dysfunction. After 1-3 days of SMG, the osteogenic markers were decreased which accompanied the decline of Fzd9 expression. Fzd9 also decreased in the femur of the rats after 3 weeks of hindlimb unloading. Overexpression of Fzd9 will counteract SMG-induced osteoblasts dysfunction. However, Fzd9 overexpression did not affect SMG induced pGSK3β and β-catenin expression or sublocalization. Overexpression of Fzd9 regulates the phosphorylation of Akt and ERK, as well as induces F-actin polymerization to form the actin cap, presses the nuclei, and increases the nuclear pore size, which promotes nuclear translocation of YAP. Our study provides mechanistic insights into the role of Fzd9 triggers actin polymerization and activates mechano-transducer YAP to rescue SMG-mediated osteoblasts dysfunction and indicates Fzd9 as a potential target to restore osteoblast function in bone diseases and space flight.