Signaling pathways associated with Lgr6 to regulate osteogenesis

Delayed fracture healing or the complete failure of bone tissue to heal (non-union) occurs with high incidence and in certain populations, such as the elderly or diabetics, the fracture incidence is even higher due to a reduced ability to form new osteoblasts, leading to less efficient bone regeneration. New therapies are needed to improve fracture management, but the molecular mechanisms governing bone healing and stem/progenitor cell proliferation and differentiation remain poorly understood. Leucine-rich repeat-containing G-protein coupled receptors are implicated in regenerating tissues with well-defined stem cell niches in stem cell-reliant organs. Using global Lgr6-null mice we recently demonstrated that Lgr6 is necessary for maintaining bone volume during adulthood and in fracture repair. Rspondins are the major ligands for Lgrs; Rspo-Lgr interaction increases cWnt signaling by preventing the turnover of Frizzled receptors. Intriguingly, we demonstrate that in Lgr6-null osteogenic cultures, cWnt-beta catenin signaling is not diminished. We performed RNA sequencing on bone marrow-derived osteogenic cultures from Lgr6-null mice and analyzed published single-cell RNA sequencing datasets to explore the molecular mechanisms regulating impaired osteogenesis and to identify cell-specific expression of Lgr6 in the bone environment. Our findings suggest that Lgr6 likely mediates osteogenesis through the Bmp pathway.