Roles of oxygen level and hypoxia-inducible factor signaling pathway in cartilage, bone and osteochondral tissue engineering.

The repair and treatment of articular cartilage injury is a huge challenge of orthopedics. Currently, most of the clinical methods applied in treating cartilage injuries are mainly to relieve pains rather than to cure them, while the strategy of tissue engineering is highly expected to achieve the successful repair of osteochondral defects. Clear understandings of the physiological structures and mechanical properties of cartilage, bone and osteochondral tissues have been established, but the understanding of their physiological heterogeneity still needs further investigation. Apart from the gradients in the micromorphology and composition of cartilage-to-bone extracellular matrixes, an oxygen gradient also exists in natural osteochondral tissue. The response of hypoxia-inducible factor (HIF)-mediated cells to oxygen would affect the differentiation of stem cells and the maturation of osteochondral tissue. This article reviews the roles of oxygen level and HIF signaling pathway in the development of articular cartilage tissue, and their prospective applications in bone and cartilage tissue engineering. The strategies for regulating HIF signaling pathway and how these strategies finding their potential applications in the regeneration of integrated osteochondral tissue are also discussed.