How vascularization is reciprocally coupled to chondrogenesis and osteogenesis in bone healing: lessons from the growth plate.

Despite considerable progress, the underlying mechanisms that enable scar-free regeneration in bone after injury are still not well understood. Here, we compared the spatiotemporal distribution of SOX9-positive chondrocytes, SPARC-positive hypertrophic chondrocytes and osteoblasts, versus Osterix-positive osteoblasts, i.e. key cell types in cartilage and bone formation, in the fracture gap of a mouse osteotomy model with the orderly sequence of events observed in the growth plate. We show that external mechanical stability determines the spatial distribution of osteoblastic and chondrogenic cell populations at day 7, thus defining the site of chondrogenesis initiation. At day 14, only rigid, but not semi-rigid fixation promoted the formation of avascular regions within previously vascularized areas. We thus propose a model how mechanical stabilization promotes bone healing: Blood vessel growth into the hematoma is followed by localized vascular degradation as chondrogenesis progresses, ultimately leading to vascular regrowth via endochondral ossification initiated at the tips of the distal bones. Deepening our understanding of these processes and how they ultimately relate to scar-free bone regeneration is of significant medical relevance as they can provide instructions how to promote fracture healing.