Prevention And Treatment Of Estrogen Deficiency Induced Osteoporosis And Promotion The Osteoporotic Bone Defect Healing By Hypoxia Mimicking Agents

The estrogen deficiency induced osteoporosis threats the health of postmenopausal women. The bone defect caused by fragility fractures is a tough problem to solve in orthopaedics. As the studies in the pathogenesis of estrogen deficiency induced osteoporosis deepen, increasing evidences indicated that the alteration in the hypoxia inducible factor-α/HIF-α singnalling pathway plays a critical role in the pathogenesis process of estrogen deficiency induced osteoporosis. Moreover, activation HIF-α singnalling pathway favors the fracture healing and bone defect healing. Dimethyloxalylglycine/DMOG, Desferrioxamine/DFO can activate HIF-α signaling pathway in normoxia, which are called “hypoxia mimicking agents”. Therefore, hypoxia mimicking agents might be explored in the prevention and treatment of estrogen deficiency induced osteoporosis and used to promote osteoporotic bone defect healing.ObjectivesTo elucidate the potential role of hypoxia mimicking agents in the prevention and treatment of estrogen deficiency induced osteoporosis and in osteoporotic bone defect healing.Methods:4. To study the effect of DMOG on the osteogenic differentiation of murine mesenchymal C3H10T1/2 and investigate the potential mechanism. 5. The osteoporosis model is established by ovariectomy(OVX). Then some OVX mice were treatment by DMOG. The femurs and blood were collected to assess the bone mineral density, bone microarchitecture, bone strength, bone turnover by micro-CT analysis, biomechanics test, elisa, realtime-PCR, westernblot and bone histomorphometry.The alteration in the HIF-α and Wnt/β-catenin signaling pathways were also uncovered. 6. The bone defect model was established by drilling a hole in the distal of the femur ofosteoporotic rat. The PLGA and PLGA loaded with DFO were inserted into the bonedefect. Micro-CT, bone histomorphometry and immunohistochemistry were employed toevaluate the bone defect healing.Results1. DMOG could activate the HIF-α signaling pathway in murine mesenchymal C3H10T1/2 cells and promote the secretion of VEGF. DMOG enhanced the expression of alkaline phosphatase and calcium deposition during the osteogenic differentiation process of C3H10T1/2 cells. Moreover, DMOG upregulated the expression of Runx-2, Osterix, β-catenin and activated Wnt/β-catenin signaling pathways. 2. The BMD, bone volume, blood volume, bone strength as well as the expression of HIF-α and β-catenin were higher in DMOG treated group than the OVX group. The bone formation was accelerated in DMOG treated group, while bone resorption remained unchanged. 3. The blood vessels in the DFO+PLGA group were significantly higher than the PLGA group at 2 weeks after surgery, and the bone volumes in DFO+PLGA group were higher than PLGA group at 2 and 4 weeks after surgery.Conclusion1. DMOG could activate HIF-α signaling pathway and promote the osteogenic differentiation of mesenchymal stem cells. 2. DMOG could prevent the bone loss in OVX mice, which were ascribed to enhanced osteogenesis and angiogenesis. 3. The PLGA loaded with DFO could boost the osteoporotic bone defect healing.