Frizzled‐9 triggers actin polymerization and activates mechano‐transducer YAP to rescue simulated microgravity‐induced osteoblast dysfunction

Long‐term spaceflight can result in bone loss and osteoblast dysfunction. Frizzled‐9 (Fzd9) is a Wnt receptor of the frizzled family that is vital for osteoblast differentiation and bone formation. In the present study, we elucidated whether Fzd9 plays a role in osteoblast dysfunction induced by simulated microgravity (SMG). After 1–7 days of SMG, osteogenic markers such as alkaline phosphatase (ALP), osteopontin (OPN), and Runt‐related transcription factor 2 (RUNX2) were decreased, accompanied by a decrease in Fzd9 expression. Furthermore, Fzd9 expression decreased in the rat femur after 3 weeks of hindlimb unloading. In contrast, Fzd9 overexpression counteracted the decrease in ALP, OPN, and RUNX2 induced by SMG in osteoblasts. Moreover, SMG regulated phosphorylated glycogen synthase kinase‐3β (pGSK3β) and β‐catenin expression or sublocalization. However, Fzd9 overexpression did not affect pGSK3β and β‐catenin expression or sublocalization induced by SMG. In addition, Fzd9 overexpression regulated protein kinase B also known as Akt and extracellular signal‐regulated kinase (ERK) phosphorylation and induced F‐actin polymerization to form the actin cap, press the nuclei, and increase nuclear pore size, thereby promoting the nuclear translocation of Yes‐associated protein (YAP). Our study findings provide mechanistic insights into the role of Fzd9 in triggering actin polymerization and activating YAP to rescue SMG‐induced osteoblast dysfunction and suggest that Fzd9 is a potential target to restore osteoblast function in individuals with bone diseases and after spaceflight. Schematic illustration of the effect of simulated microgravity (SMG)‐regulated Fzd9 on YAP nuclear translocation in rescue osteoblast dysfunction. The overexpression of Fzd9 regulates the phosphorylation of ERK and Akt, as well as induces F‐actin polymerization to form the actin cap, pressing the nuclei, and increasing the nuclear pore size, which then promotes nuclear translocation of YAP. Our study findings indicate that Fzd9 acted as a potential target to restore osteoblast functions in bone diseases and space flight.