Tracing the skeletal progenitor transition during postnatal bone formation

Multiple distinct types of skeletal progenitors have been shown to contribute to endochondral bone development and maintenance. However, the division of labor and hierarchical relationship between different progenitor populations remain undetermined. Here we developed dual-recombinase fate-mapping systems to capture the skeletal progenitor transition during postnatal bone formation. We showed that postnatal osteoblasts arose primarily from chondrocytes before adolescence and from Lepr⁺ bone marrow stromal cells (BMSCs) after adolescence. This transition occurred in the diaphysis during adolescence and progressively spread to the metaphysis. The osteoblast-forming Lepr⁺ BMSCs derived primarily from fetal Col2⁺ cells. Conditional deletion of Runx2 from perinatal chondrocytes and adult Lepr⁺ BMSCs impaired bone lengthening and thickening, respectively. Forced running increased osteoblast formation by perinatal chondrocytes but not by adult Lepr⁺ BMSCs. Thus, the short-term developmental skeletal progenitors generated the long-term adult skeletal progenitors. They sequentially control the growth and maintenance of endochondral bones.