Investigation On The Role And Mechanism Of Hypoxia/HIF-1?Pathway In Bone Remodeling

Bone tissue maintains its bone mass and builds its characteristics through continuous bone remodeling.Mesenchymal stem cells,osteoblasts,osteoclasts and osteocytes are the main effector cells in bone remodeling.Any abnormal biological functions of these cells can cause diseases such as osteoporosis,osteolysis,and bone sclerosis.In view of the development of bone tissue is carried out in the low oxygen state,and the effector cells that involved in the process of bone remodeling are oxygen-sensing cells,so it is important to study the role of hypoxia/HIF-1? pathway and its related mechanisms in bone remodeling.OBJECTIVEThis study was to elucidate the effect the activation of hypoxia/HIF-1? pathway in bone remodeling,and to explore the role of the related mechanism of hypoxia/HIF-1? pathway in different disease models.METHODS(1)This research used tissue morphological staining,cell culture,real-time PCR,western blot,luciferase reporter gene and other methods to elucidate the effect of osteoblasts activated by hypoxia / HIF-1? pathway on the biological behavior of osteoclasts and its mechanism.(2)This research used micro-CT,histomorphological staining,cell culture,real-time PCR,western blot and other methods to evaluate the effect of micro RNA-34a-5p on the biological function of bone marrow mesenchymal stem cells.(3)This research used micro-CT,histomorphological staining,cell culture,real-time PCR,western blot and other methods to evaluate the effect of DFO on the biological function of osteoclast.RESULTS(1)After Vhl knocked out,hypoxia/HIF-1? pathway was activated,IL-33 expression was up-regulated.The accumulation of HIF-1? in osteoblast directly regulated the transcriptional activity of IL-33 promoter.Osteoblasts could inhibit the production,activity and bone resorption of osteoclasts by secreting IL-33.IL-33 could inhibit the differentiation of osteoclast by up-regulating the expression of micro RNA-34a-5p in osteoclast precursor cells.(2)Glucocorticoid inhibited the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.Glucocorticoid could regulate the expression of micro RNA-34a-5p in bone marrow mesenchymal stem cells in both directions.Intervention of micro RNA-34a-5p expression could inhibit the inhibitory effect of glucocorticoid on bone marrow mesenchymal stem cells.(3)DFO inhibited osteoclastogenesis,activity and bone resorption.DFO up-regulated the expression of HO-1in osteoclast precursor cells.Inhibition of P38 MAPK pathway enhanced the up-regulation of HO-1by DFO.DFO could reduce particle-induced osteolysis by inhibiting the inflammatory osteoclastogenesis.CONCLUSIONS(1)Osteoblasts could up-regulate the expression of micro RNA-34a-5p in osteoclasts by activating hypoxia/HIF-1?/IL-33 pathway and inhibit the differentiation of bone marrow mononuclear cells into osteoclasts.(2)Glucocorticoid could inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells by regulating the expression of micro RNA-34a-5p in bone marrow mesenchymal stem cells.(3)DFO could up-regulate the expression of HO-1 in the bone precursor cells through the P38 MAPK signaling pathway,and reduce the osteolysis induced by the polystyrene particles through inhibiting osteoclastogenesis.