Hypoxia-driven pathways in endochondral bone development

Endochondral ossification, the mechanism responsible for the development of the long bones, is dependent on the vigorous and tightly regulated proliferation, differentiation, and matrix synthesis by chondrocytes and osteoblasts. Chondrocytes first generate cartilaginous templates of the forming bones from mesenchymal condensations and subsequently create the growth plates that provide the prime engine for bone growth. These cartilaginous structures are inherently avascular and represent physiologically hypoxic tissues. Hypoxia-driven pathways, governed by the hypoxia-inducible factors (HIFs), are absolutely essential for the survival and functioning of chondrocytes in these challenging conditions. Following chondrogenesis, further bone development and growth is driven by the progressive conversion of the prefiguring cartilage into bone tissue. This process depends on cartilage neovascularization and the concomitant infiltration of the future ossified region by osteoprogenitors, and is molecularly steered by the potent angiogenic stimulator vascular endothelial growth factor (VEGF). Later in life, HIFs and VEGF remain vital players in the regulation of bone remodeling, in line with the hypoxic status of the postnatal bone and marrow environment. HIF-mediated signaling has also been implicated in joint formation and the integrity of the adult articular cartilage. Thus, the oxygen-regulated genetic program mediated by HIFs is a key to the controlled development, growth, health, and disease of endochondral bones. Much of the current knowledge is based on the investigation of a growing number of genetically modified mouse models, dissecting the roles of the HIFs as well as their key downstream effectors and upstream regulators in mesenchymal progenitors, chondrocytes, and osteoblast lineage cells, as will be reviewed in this chapter.