The regeneration process has generally been characterized by four steps including inflammation phase with hematoma, cartilage callus formation, bony callus formation and bone remodeling. During bone regeneration, angiogenesis is essential and depends on hypoxic stimuli and production of proangiogenic factors such as vascular endothelial growth factor, Erythropoietin, fibroblast growth factor, transforming growth factor-beta and insulin like growth factor. The bone cells are readily located in a hypoxic microenvironment during development and regeneration. Hypoxia inducible factor-a is identified as key mediator for cell adaptation to low SDM25N hydrochloride oxygen tension. VEGF and EPO are established downstream targets of HIF-a. It is well established that VEGF is expressed in osteoblasts and the HIF-a/VEGF pathway couples angiogenesis and osteogenesis during bone development and regeneration while the study on the involvement of EPO in bone regeneration is just emerging. EPO is a 34 kD circulating glycoprotein hormone which is initially recognized as the crucial growth factor that controls red blood cell development in bone marrow through binding to its high affinity receptor expressed on erythroid progenitor cells. EPO is predominantly produced by the interstitial fibroblasts of the renal cortex and outer medulla in adult animals, and by Kuffer��s cells in the liver during embryonic development, under the control of oxygen sensing HIF pathway. In addition to its principal function in erythropoiesis, nonehematopoietic functions of EPO such as angiogenic, cardioprotective, neuroprotctive and neurotrophic effects have raised great interest and been extensively studied, due to the findings that EPO is also produced in non-renal tissues such as brain, and that EPOR is present in a variety of nonhematopoietic cell types such as brain capillary endothelial cells, vascular smooth muscle cells, myocardial cells, neurons and astrocytes. The potential physiological effects of EPO on skeletal tissue were suggested by both clinical and animal studies that bone modulation was associated with erythropoiesis stimulation by systemic administration of EPO. However, the underlying mechanism is largely unknown. It was reported that EPO activated JAK/STAT SCH 28080 signaling in hematopoietic stem cells to produce bone morphogenetic proteins and thus exerted indirect function in bone formation.