The Possible Mechanism Of Regulating The New Bone Formation And Bone Remodeling By VEGFR Inhibitor PTK787

Objective:The process of bone remodeling and bone regeneration is coordinated by osteoblastic bone formation and osteoclastic bone resorption. Angiogenesis is a key factor in bone remodeling and bone regeneration. VEGF, the key angiogenic factor, has been proved to be involved in angiogenesis and bone formation. PTK787 is a potent inhibitor of VEGFR, which can block the VEGF/VEGFR signaling pathways. In this study, PTK787 was continually introduced topically using micro-osmotic pump to the rat skull critical bone defects. The effect on new bone formation and bone remodeling and possible regulatory mechanisms by PTK787 were studied. Methods:32 adult male Sprague-Dawley(SD) rats were randomly divided into four groups. Two 5 mm critical bone defects on both sides of parietal bone were made. The bone defect on the right side(experimental side) was given by 13.125 mg of PTK787 through micro-osmotic pumps at 1μl / h for 7 days and the left side(control side) without PTK787 respectively(5% DMSO+1% Tween80+94% distilled water only). Rats were euthanized at 3, 7, 14 and 28 days. Immunohistochemical staining was used to detect the expression and integrated optical density(IOD) of BMP-2, TGF-β1. The expression and IOD of TRAP and RANKL were evaluated, followed by semi-quantitative statistical analysis.Results :The data showed that at 3 and 7 days time points, the positive expressions of BMP-2, TGF-β1 and RANKL in the control group were higher than those in the experimental group, the difference has statistically significant. At 14 days after surgery, the positive expression of TGF-β1 and the osteoclast activity in the control group were significantly higher than those in the experimental group. At 28 days, the osteoclast activity in the control group was significantly higher than those in the experimental group. At the 14 days and 28 days after surgery, IOD of RANKL was higher in the experimental group, although no statistically significant could be found. Conclusion:It was concluded that PTK787, which can inhibit the binding of VEGF and VEGFR, has effect on the bone growth factor activity and osteoclast activity. PTK787 is involved in the new bone formation and bone remodeling by regulating osteoblast activity and osteoclast activity.