Bone marrow and periosteal skeletal stem/progenitor cells make distinct contributions to bone maintenance and repair

A fundamental question in bone biology concerns the contributions of skeletal stem/progenitor cells (SSCs) in the bone marrow versus the periosteum to bone repair. We found that SSCs in adult bone marrow can be identified based on Lepr^cre and Adiponectin-cre/creER expression while SSCs in adult periosteum can be identified based on Gli1^creERT2 expression. Under steady-state conditions, new bone arose primarily from bone marrow SSCs. After bone injuries, both SSC populations began proliferating but made very different contributions to bone repair. Drill injuries were primarily repaired by LepR⁺/Adiponectin⁺ bone marrow SSCs. Conversely, bicortical fractures were primarily repaired by Gli1⁺ periosteal SSCs, though LepR⁺/Adiponectin⁺ bone marrow cells transiently formed trabecular bone at the fracture site. Gli1⁺ periosteal cells also regenerated LepR⁺ bone marrow stromal cells that expressed hematopoietic niche factors at fracture sites. Different bone injuries are thus repaired by different SSCs, with periosteal cells regenerating bone and marrow stroma after non-stabilized fractures.