Role and regulation of vascularization processes in endochondral bones

Adequate vascularization is an absolute requirement for bone development, growth, homeostasis, and repair. Endochondral ossification during fetal skeletogenesis is typified by the initial formation of a prefiguring cartilage template of the future bone, which itself is intrinsically avascular. When the chondrocytes reach terminal hypertrophic differentiation they become invaded by blood vessels. This neovascularization process triggers the progressive replacement of the growing cartilage by bone, in a complex multistep process that involves the coordinated activity of chondrocytes, osteoblasts, and osteoclasts, each standing in functional interaction with the vascular system. Studies using genetically modified mice have started to shed light on the molecular regulation of the cartilage neovascularization processes that drive endochondral bone development, growth, and repair, with a prime role being played by vascular endothelial growth factor and its isoforms. The vasculature of bone remains important throughout life as an intrinsic component of the bone and marrow environment. Bone remodeling, the continual renewal of bone by the balanced activities of osteoclasts resorbing packets of bone and osteoblasts building new bone, takes place in close spatial relationship with the vascular system and depends on signals, oxygen, and cellular delivery via the bloodstream. Conversely, the integrity and functionality of the vessel system, including the exchange of blood cells between the hematopoietic marrow and the circulation, rely on a delicate interplay with the cells of bone. Here, the current knowledge on the cellular relationships and molecular crosstalk that coordinate skeletal vascularization in bone development and homeostasis will be reviewed.