The Mechanism Study On BMP-2 Activated Smad1 And P65 To Promote Osteoclast Activation And Induce Osteolysis

Background: the use of recombinant human bone morphogenetic protein-2(rhBMP-2)to enhance lumbar spine fusion and repair bone defect has gained popularity after Food and Drug Administration of the United States approved its use in 2002.However,the development of vertebral osteolysis was found by numerous retrospective studies and still unresolved.The current studies suggest that the occurrence of osteolysis may be related to osteoclasts' activation promoted by BMP-2,however the mechanisms are not yet clear.Methods: first we observed the effects of BMP-2 on bone in vivo by injecting a lentivirus which overexpressing BMP-2 into the C57 mouse tibia.Second,we established BMP-2 induced ectopic osteogenesis model and observed bone resorption in heterotopic bone tissue.M-CSF and RANKL with different concentration of BMP-2(0 ng/ml,30 ng/ml,60 ng/ml and 90 ng/ml)were used to induce bone marrow-derived macrophages(BMMs)differentiating into osteoclasts,and BMP-2's effect on osteoclast differentiation,gene expression and bone resorption were observed in vitro.Furthermore,we detected the expression of Smad1 and NF-?B signaling pathway related proteins,and finally explored the role of BMP receptors in the regulation of osteoclast differentiation by BMP-2.Results: the results showed that BMP-2 could induce bone resorption in the tibia of mice in vivo,so that the bone volume fraction,trabecular number and trabecular thickness decreased.BMP-2 also activates osteoclasts while inducing ectopic osteogenesis,leading to bone resorption.In vitro BMP-2 can promote RANKL induced osteoclast differentiation and enhance osteoclast's resorption function.By activating the Smad signaling pathway,rhBMP-2 can increase the phosphorylation of Smad and promote the degradation of I?B?,which results in accelerating the phosphorylation of p65 and entering the nucleus.The BMP receptors,especially the synergistic action of BMPR 2 and RANK plays a significant role in this process.Conclusion: our results initially demonstrate the mechanism of BMP-2 induced osteolysis and offer an important theoretical basis for the rational use of BMP-2 clinically.