Wnt-associated adult stem cell marker Lgr6 is required for osteogenesis and fracture healing

Despite the remarkable regenerative capacity of skeletal tissues, nonunion of bone and failure of fractures to heal properly presents a significant clinical concern. Stem and progenitor cells are present in bone and become activated following injury; thus, elucidating mechanisms that promote adult stem cell-mediated healing is important. Wnt-associated adult stem marker Lgr6 is implicated in the regeneration of tissues with well-defined stem cell niches in stem cell-reliant organs. Here, we demonstrate that Lgr6 is dynamically expressed in osteoprogenitors in response to fracture injury. We used an Lgr6-null mouse model and found that Lgr6 expression is necessary for maintaining bone volume and efficient postnatal bone regeneration in adult mice. Skeletal progenitors isolated from Lgr6-null mice have reduced colony-forming potential and reduced osteogenic differentiation capacity due to attenuated cWnt signaling. Lgr6-null mice consist of a lower proportion of self-renewing stem cells. In response to fracture injury, Lgr6-null mice have a deficiency in the proliferation of periosteal progenitors and reduced ALP activity. Further, analysis of the bone regeneration phase and remodeling phase of fracture healing in Lgr6-null mice showed impaired endochondral ossification and decreased mineralization. We propose that in contrast to not being required for successful skeletal development, Lgr6-positive cells have a direct role in endochondral bone repair.