Transdifferentiation of hypertrophic chondrocytes during endochondral bone repair by activation of pluripotent stem cell programs (216.1)

Abstract

The majority of bone fractures heal by endochondral ossification, where bone forms secondarily to cartilage. Mechanistically bone repair is presumed to parallel endochondral ossification during development. Dogma holds that chondrocytes mature to hypertrophy, undergo apoptosis, and bone forms by invading osteoprogenitors. However, we have data to suggest chondrocytes transform directly into bone during regeneration. Consequently, we propose an alternate hypothesis where transdifferentiation of chondrocytes into osteocytes plays a direct role in endochondral bone regeneration. Using lineage tracing to follow cartilage transplanted into segmental bone defects created in murine tibiae, we demonstrate the vast majority of osteocytes are cartilage derived. Hypertrophic chondrocytes in the fracture callus are mineralized and express classic bone markers, without significant apoptosis. Instead some “transitioning” chondrocytes express Oct4A and sox‐2, suggesting that activation of the pluripotent programs may facilitate phenotypic transformation. Histologically this process appears coordinated by the invading vasculature and mineralization of cartilage can be fully recapitulated in vitro using endothelial cell conditioned medium. Taken together, these data suggest that there may be significant differences between endochondral ossification during bone development and repair.Grant Funding Source: NIH NRSA F32 (Bahney), MTF Junior Investigator Award (Bahney), NIH #AR053645 & AR057 (TM)