Final Report Summary - ANGIOBONE (Angiogenic growth, specialization, ageing and regenerationof bone vessels) The skeleton and its vasculature form a functional unit with great relevance in health, regeneration, and disease. Nevertheless, some of the even most fundamental aspects of vessel growth, specialization, the spatial distribution of arterioles and the consequences for bone perfusion, or the changes occurring during ageing and in pathological settings had remained unknown. We have used a powerful combination of mouse genetics, fate mapping, transcriptional profiling, computational biology, confocal and two-photon microscopy, micro-CT imaging, biochemistry and cell biology methods to characterize the growth, differentiation, dynamics, and ageing of the bone vasculature. This has uncovered the existence of functionally specialized endothelial cell subpopulations, which release growth factors and other molecular signals, support perivascular bone-forming (osteoprogenitor) cell populations, and thereby couple vessel growth to bone formation. We also discovered strong age-related changes in the bone vasculature and vessel-associated mesenchymal cells. In a proof-of-principle experiment, we demonstrated that the activation of Notch signalling in the endothelium of aged mice is sufficient for the induction of vessel growth, the re-emergence of perivascular osteoprogenitor cells and an increase in mineralized bone. Based on the results of this project, we conclude that endothelial cells play central roles in bone growth, homeostasis and regeneration. We also propose that bone endothelial cells might be a promising target for the treatment of age-related bone loss or osteoporosis.
