Foxk2 regulates osteoblast differentiation and bone formation through Slc1a4-mediated enhancement of glutamine-dependent energy metabolism

Abstract Foxk2 can regulate cell differentiation, proliferation, metabolism and tumor fate. However, the roles of Foxk2 in bone formation are unknown. Here, we found that global knockout of Foxk2 in mice resulted in decreased bone mass and bone formation. Deletion of Foxk2 in primary pre-osteoblasts suppressed osteoblast differentiation in vitro and conditional knockout of Foxk2 in pre-osteoblasts in mice showed attenuated bone mass and bone formation. Notably, overexpression of Foxk2 in pre-osteoblasts alleviated bone loss in mice caused by ovariectomy. Mechanistically, we identified Slc1a4 as a downstream target of Foxk2 through joint analysis the data of RNA-Seq and CUT&Tag. Knockout of Slc1a4 in pre-osteoblasts in mice resulted in decreased bone mass and bone formation. Overexpression of Slc1a4 in pre-osteoblasts alleviated bone loss and damaged bone formation caused by Foxk2 deletion. Furthermore, metabolomic analyses highlighted the role for Foxk2 in promoting glutamine-dependent energy metabolism mediated by Slc1a4, which is required for osteoblast differentiation. In summary, our study demonstrated that Foxk2 promotes osteoblast differentiation and bone formation through Slc1a4-mediated enhancement of glutamine-dependent energy metabolism, which is also a promising target for preventing osteoporosis.