Mapk7 regulates bone-fat balance by targeting Lrp6/ß-catenin axis

The lineage commitment and differentiation of mesenchymal stem cells (MSCs) play a crucial role in the maintenance of bone stability. MAPK7 (Mitogen-activated protein kinase 7), a member of the MAPK family, controls cell proliferation, differentiation, and survival. However, the specific role of Mapk7 in regulating the osteogenic and adipogenic differentiation of MSCs remains to be determined. In this study, depletion of Mapk7 in MSCs (Prx1-Cre) resulted in severe low bone mass and accumulation of bone marrow fat in mice exhibiting osteoporosis. In vitro, overexpression of Mapk7 in MSCs induced an enhancement of osteogenesis in MSCs, while adipogenesis was attenuated. Mechanistically, MAPK7 availed to influence the activity of WNT/ß-catenin signaling by modulating the phosphorylation of LRP6 ser1490, which ultimately impacted the osteogenic-adipogenic differentiation fate of MSCs for the first time. This is of great clinical and scientific significance for understanding the biological function of Mapk7 gene and developing new therapeutic targets for OP. Our study for the first time demonstrates that Mapk7/Lrp6/ß-catenin signal axis plays a critical role in regulating the osteogenic and adipogenic differentiation of MSCs. It also suggests that modulating the function of Mapk7 may benefit the treatment of MSCs differentiation inbalance related bone diseases such as osteoporosis. Overall design: To explore the molecular mechanism of Mapk7 in regulation of osteoblast-adipocyte lineage transition, we extracted RNA from same generation of MSCs in WT (3 week) and CKO (3 week) mice for RNA-seq