载辛伐他汀聚合物对剩余牙槽嵴骨修复影响的实验研究
摘要
剩余牙槽嵴骨吸收严重影响患者的美观和进一步功能修复。目前关于药物防治方面的报道较少。本实验研究在国家自然科学基金资助下(项目编号:30471893),通过观察降低外周血胆固醇辛伐他汀药物对大鼠剩余牙槽嵴骨修复的影响,探讨以聚乳酸-羟基乙酸高分子聚合物[poly(lactide-co-glycolide),PLGA]作为辛伐他汀载体的可能性,并通过体内外研究初步探讨其作用机制。
本实验首先拔除大鼠下颌中切牙后,通过组织学和影像学方法,确认该模型可作为大鼠剩余牙槽嵴骨吸收的动物模型;其次,将辛伐他汀溶解于PLGA的有机溶液中,采用溶剂挥发法合成与制备载辛伐他汀PLGA支架材料;第三,局部应用载辛伐他汀PLGA对所建立的Wistar大鼠下颌切牙拔除后剩余牙槽嵴骨吸收动物模型进行研究,采用组织学、免疫组织化学和分子杂交等手段,定性结合定量评价载辛伐他汀PLGA对剩余牙槽嵴骨修复的影响。研究结果表明,局部应用辛伐他汀通过增加拔牙窝内TGF-β、BMP-2和VEGF信号分子的表达促进成骨,加速和提高新骨形成速度与质量。
本研究的创新点在于克服辛伐他汀全身给药的副作用,率先以局部缓释药物的形式将辛伐他汀用于剩余牙槽嵴骨修复方面的研究。为进一步应用于临床防治剩余牙槽嵴萎缩提供科学的理论和实验依据。
Residual Ridge Resorption (RRR) as the result of tooth lost caused by many etiological factors, will lead to difficulty of prosthetic restoration, disturbed masticatory function and facial cosmetic. Insufficient masticatory function may affect the blood supply for vital organs such as heart and brain; therefore, the prevention and treatment of RRR are meaningful theoretically and practically, and this approach is of importance in maintaining bodily health as well as local health in oral cavity. Nowadays, there are some studies focusing on the surgical treatment such as autografts, allografts, osteopromotion by the guided bone regeneration technique, immediate placement of dental implants. However, the pharmaceutical therapy of RRR after tooth lost is less reported. Statins are competitive inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, and have been widely used to decrease blood cholesterol and prevent heart and blood vessel diseases. Since Mundy first reported that statins stimulated in vivo bone formation in rodents and suggested that this effect was associated to the increased expression of the bone morphogenetic protein-2 in osteoblast and marrow mesenchymal stem cell, many studies utilizing statins to treat osteoporosis, bone fracture and bone lesion were carried out. However, there is no detailed report about the preventive effect of simvastatin on RRR after tooth lost until now.
Because simvastatin undergoes extensive first-pass extraction in the liver after oral administration, the availability of the drug to the general circulation is 2.4% and even lower in bone tissue; its local concentration is too low to induce bone formation. In this study, the possibility and underlying mechanism of preventive effect of simvastatin on RRR with the PLGA as carrier was explored in RRR model created by extraction of lower incisors in Wistar rat.
This research is a serial study and includes five parts as follow:
1. To develop a safe method to extract the lower incisors without extra injury in rat. The prominent decrease in residual ridge height after 4 weeks of tooth extraction was found by soft x-ray investigation. In histological study, the newly formed bone could be found after 2 weeks of tooth extraction with the degradation of residual blood clot in extraction socket. After 4 weeks of extraction, active bone remodeling could be observed and after 8 weeks, the extraction socket was full of newly formed bone. After 12 weeks, there was no obvious boundary between the matured new bone and surrounding alveolar bone. This healing procedure is similar to that of humans morphologically and histologically. This result showed that this rat model can be used as the counterpart of human residual ridge resorption in research. 2. To explore the effects of porous polylactic acid/polyglycolic acid copolymer (PLGA) implanted into extraction socket on the regeneration of alveolar bone in rats. The results showed that the implantation of degradable hydrophobic polymer did not significantly alter the process of bone healing, and it can preserve the length and width of residual ridge. The new material is of good biocompatibility, biodegradability, stability, osteoconduction.③To produce the simvastatin- PLGA scaffold by solvent volatilixation method at the first time and the property of slow releasing of simvastatin from scaffold was testified by in vitro study. In experimental group, the simvastatin-PLGA scaffold was implanted into the tooth socket, and in control group the PLGA scaffold was used. The findings manifested that the relative residual ridge height in experimental group was significantly higher than that of control group after 14, 28, 56, 84 days of implantation, and the bone mineral density (BMD) in experimental group was significantly higher than that of control group after 28, 56, 84 days of implantation with soft x-ray analysis, BMD measurement and histological observation. In addition the higher rate and better quality of new bone formation in experimental group was observed. This result showed that the simvastatin-PLGA scaffold could promote the restoration of bone injury effectively. 4. To evaluate the differential effect of simvastatin on the expression of TGFβ1, BMP2 and VEGF between experimental and control group in tooth socket with the immunohistochemistry and in situ hybridization. The results displayed that the numbers of TGFβ1, BMP2 and VEGF positive undifferentiated mesenchymal cells, osteoblasts and vascular endothelial cells in experimental group was significantly higher than that in control group after 1 and 2 weeks of implantation. After 4 weeks of implantation, the number of TGFβ1 and BMP2 but not VEGF positive cells in experimental group was significantly higher than that of control group. Brdu positive cells in experimental group were significantly higher than that in control group after 5 and 7 days of implantation. This finding showed that simvastatin promoted proliferation of mesenchymal cells and osteoblastic cells in tooth socket. The results in situ hybridization showed that topic application of simvastatin could increase the expression of TGFβ1、BMP2 and VEGFmRNA,which promote the healing of tooth socket. 5. To explore the osteoinductive mechanism of simvastatin in vitro. DMSO (for control group) and DMSO solution with the simvastatin at different concentrations (for experimental groups) were added to osteoblast which differentiated from marrow mesenchymal cell. The expression of Osterix, OPG and PC-1 in all groups was evaluated with RT-PCR and Western-Blot technique after 72 hours. The findings showed that the expression of Osterix in experimental groups with the simvastatin concentration at 0.1、0.2、0.5μmol/L was significantly upregulated and the expression of OPG and PC-1 was significantly increased with the simvastatin concentration at 1.0μmol/L compared with that in control groups . The results manifested that the simvastatin can promote the new bone formation and mediate the bone calcification procedure by augmenting the expression of Osterix, OPG and PC-1; in addition, the effect of simvastatin depends on its concentration.
This study evaluated the effect of simvastatin on Osterix expression in osteoblast by Western-Blot technique for the first time. The findings displayed that expression level of Osterix in experimental group was significantly higher than that in control group after 72 hours of simvastatin application, and in a certain range of concentration (0.1μmol/L, 0.2μmol/L, 0.5μmol/L), the ability of promoting Osterix expression was dose dependent. Hence we confirmed that the simvastatin can promote the differentiation from preosteoblast to osteoblast and the consequential new bone formation by regulating Osterix pathway.
Taken all the results of in vivo and in vitro studies into consideration, simvastatin-PLGA scaffold can promote new bone formation, increase BMD and prevent the RRR. Its mechanism depends on the promotion of new bone formation by upregulating the expression of TGFβ,BMP2,VEGF and Osterix, suppressing the osteoclastic differentiation by promoting OPG expression, and mediating the calcification by regulating PC-1 expression. Namely, the simvastatin can promote alveolar bone restoration in tooth socket and prevent RRR by regulating the expression of many cytokines and growth factors, which will mediate the transcription and translation of target gene through several signal pathways. The selective effect of different concentration of simvastatin on the differential expression of different cytokines implied that the effective dosage should be determined cautiously after comprehensive analysis of its biological effect when it is used to promote new bone formation in clinic.
The creativity of this study is to verify that the simvastatin-PLGA scaffold with slow releasing ability can promote the healing of extraction socket and prevent the RRR for the first time. The osteoinductive mechanism of simvastatin-PLGA scaffold was studied by the combination of in vivo and in vitro study with the techniques of soft x-ray, histology, cell biology and molecular biology.
本实验首先拔除大鼠下颌中切牙后,通过组织学和影像学方法,确认该模型可作为大鼠剩余牙槽嵴骨吸收的动物模型;其次,将辛伐他汀溶解于PLGA的有机溶液中,采用溶剂挥发法合成与制备载辛伐他汀PLGA支架材料;第三,局部应用载辛伐他汀PLGA对所建立的Wistar大鼠下颌切牙拔除后剩余牙槽嵴骨吸收动物模型进行研究,采用组织学、免疫组织化学和分子杂交等手段,定性结合定量评价载辛伐他汀PLGA对剩余牙槽嵴骨修复的影响。研究结果表明,局部应用辛伐他汀通过增加拔牙窝内TGF-β、BMP-2和VEGF信号分子的表达促进成骨,加速和提高新骨形成速度与质量。
本研究的创新点在于克服辛伐他汀全身给药的副作用,率先以局部缓释药物的形式将辛伐他汀用于剩余牙槽嵴骨修复方面的研究。为进一步应用于临床防治剩余牙槽嵴萎缩提供科学的理论和实验依据。
Residual Ridge Resorption (RRR) as the result of tooth lost caused by many etiological factors, will lead to difficulty of prosthetic restoration, disturbed masticatory function and facial cosmetic. Insufficient masticatory function may affect the blood supply for vital organs such as heart and brain; therefore, the prevention and treatment of RRR are meaningful theoretically and practically, and this approach is of importance in maintaining bodily health as well as local health in oral cavity. Nowadays, there are some studies focusing on the surgical treatment such as autografts, allografts, osteopromotion by the guided bone regeneration technique, immediate placement of dental implants. However, the pharmaceutical therapy of RRR after tooth lost is less reported. Statins are competitive inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, and have been widely used to decrease blood cholesterol and prevent heart and blood vessel diseases. Since Mundy first reported that statins stimulated in vivo bone formation in rodents and suggested that this effect was associated to the increased expression of the bone morphogenetic protein-2 in osteoblast and marrow mesenchymal stem cell, many studies utilizing statins to treat osteoporosis, bone fracture and bone lesion were carried out. However, there is no detailed report about the preventive effect of simvastatin on RRR after tooth lost until now.
Because simvastatin undergoes extensive first-pass extraction in the liver after oral administration, the availability of the drug to the general circulation is 2.4% and even lower in bone tissue; its local concentration is too low to induce bone formation. In this study, the possibility and underlying mechanism of preventive effect of simvastatin on RRR with the PLGA as carrier was explored in RRR model created by extraction of lower incisors in Wistar rat.
This research is a serial study and includes five parts as follow:
1. To develop a safe method to extract the lower incisors without extra injury in rat. The prominent decrease in residual ridge height after 4 weeks of tooth extraction was found by soft x-ray investigation. In histological study, the newly formed bone could be found after 2 weeks of tooth extraction with the degradation of residual blood clot in extraction socket. After 4 weeks of extraction, active bone remodeling could be observed and after 8 weeks, the extraction socket was full of newly formed bone. After 12 weeks, there was no obvious boundary between the matured new bone and surrounding alveolar bone. This healing procedure is similar to that of humans morphologically and histologically. This result showed that this rat model can be used as the counterpart of human residual ridge resorption in research. 2. To explore the effects of porous polylactic acid/polyglycolic acid copolymer (PLGA) implanted into extraction socket on the regeneration of alveolar bone in rats. The results showed that the implantation of degradable hydrophobic polymer did not significantly alter the process of bone healing, and it can preserve the length and width of residual ridge. The new material is of good biocompatibility, biodegradability, stability, osteoconduction.③To produce the simvastatin- PLGA scaffold by solvent volatilixation method at the first time and the property of slow releasing of simvastatin from scaffold was testified by in vitro study. In experimental group, the simvastatin-PLGA scaffold was implanted into the tooth socket, and in control group the PLGA scaffold was used. The findings manifested that the relative residual ridge height in experimental group was significantly higher than that of control group after 14, 28, 56, 84 days of implantation, and the bone mineral density (BMD) in experimental group was significantly higher than that of control group after 28, 56, 84 days of implantation with soft x-ray analysis, BMD measurement and histological observation. In addition the higher rate and better quality of new bone formation in experimental group was observed. This result showed that the simvastatin-PLGA scaffold could promote the restoration of bone injury effectively. 4. To evaluate the differential effect of simvastatin on the expression of TGFβ1, BMP2 and VEGF between experimental and control group in tooth socket with the immunohistochemistry and in situ hybridization. The results displayed that the numbers of TGFβ1, BMP2 and VEGF positive undifferentiated mesenchymal cells, osteoblasts and vascular endothelial cells in experimental group was significantly higher than that in control group after 1 and 2 weeks of implantation. After 4 weeks of implantation, the number of TGFβ1 and BMP2 but not VEGF positive cells in experimental group was significantly higher than that of control group. Brdu positive cells in experimental group were significantly higher than that in control group after 5 and 7 days of implantation. This finding showed that simvastatin promoted proliferation of mesenchymal cells and osteoblastic cells in tooth socket. The results in situ hybridization showed that topic application of simvastatin could increase the expression of TGFβ1、BMP2 and VEGFmRNA,which promote the healing of tooth socket. 5. To explore the osteoinductive mechanism of simvastatin in vitro. DMSO (for control group) and DMSO solution with the simvastatin at different concentrations (for experimental groups) were added to osteoblast which differentiated from marrow mesenchymal cell. The expression of Osterix, OPG and PC-1 in all groups was evaluated with RT-PCR and Western-Blot technique after 72 hours. The findings showed that the expression of Osterix in experimental groups with the simvastatin concentration at 0.1、0.2、0.5μmol/L was significantly upregulated and the expression of OPG and PC-1 was significantly increased with the simvastatin concentration at 1.0μmol/L compared with that in control groups . The results manifested that the simvastatin can promote the new bone formation and mediate the bone calcification procedure by augmenting the expression of Osterix, OPG and PC-1; in addition, the effect of simvastatin depends on its concentration.
This study evaluated the effect of simvastatin on Osterix expression in osteoblast by Western-Blot technique for the first time. The findings displayed that expression level of Osterix in experimental group was significantly higher than that in control group after 72 hours of simvastatin application, and in a certain range of concentration (0.1μmol/L, 0.2μmol/L, 0.5μmol/L), the ability of promoting Osterix expression was dose dependent. Hence we confirmed that the simvastatin can promote the differentiation from preosteoblast to osteoblast and the consequential new bone formation by regulating Osterix pathway.
Taken all the results of in vivo and in vitro studies into consideration, simvastatin-PLGA scaffold can promote new bone formation, increase BMD and prevent the RRR. Its mechanism depends on the promotion of new bone formation by upregulating the expression of TGFβ,BMP2,VEGF and Osterix, suppressing the osteoclastic differentiation by promoting OPG expression, and mediating the calcification by regulating PC-1 expression. Namely, the simvastatin can promote alveolar bone restoration in tooth socket and prevent RRR by regulating the expression of many cytokines and growth factors, which will mediate the transcription and translation of target gene through several signal pathways. The selective effect of different concentration of simvastatin on the differential expression of different cytokines implied that the effective dosage should be determined cautiously after comprehensive analysis of its biological effect when it is used to promote new bone formation in clinic.
The creativity of this study is to verify that the simvastatin-PLGA scaffold with slow releasing ability can promote the healing of extraction socket and prevent the RRR for the first time. The osteoinductive mechanism of simvastatin-PLGA scaffold was studied by the combination of in vivo and in vitro study with the techniques of soft x-ray, histology, cell biology and molecular biology.
引文
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