Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone

The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass. Bone homeostasis and repair declines with ageing and the mechanisms regulating the relationship between bone growth and blood vessel formation have remained unknown; this mouse study identifies the endothelial cells that promote the formation of new bone, a small microvessel subtype that can be identified by high CD31 and high Emcn expression. There is evidence to suggest that blood vessels, particularly their endothelial cells, control the growth, homeostasis and regeneration of organs. In two papers published in this issue of Nature, Ralf Adams and colleagues demonstrate that the bone vasculature contains endothelial cells specialized to support bone maturation and regeneration. Anjali Kusumbe et al. identify a capillary subtype in the mouse skeletal system that has a key role in mediating bone growth. These vessels contain so-called type H endothelial cells that preferentially associate with osteoprogenitors and are reduced during ageing. Hypoxia-inducible factor 1α (HIF-1α) is shown to be crucial in maintaining the type H cells, and the fact that these cells are lost in aged animals suggests that loss of HIF-1α signalling may be involved in age-related bone changes. In the second paper, Saravana Ramasamy et al. show that blood vessel growth in bone requires Notch signalling and involves a specialized form of angiogenesis that does not involve endothelial sprouts.