Sonic hedgehog基因对对植体周围骨缺损修复的影响
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摘要
由于肿瘤、外伤、先天性疾病或严重的牙周炎等造成的牙槽骨缺损直接影响口腔修复重建。在牙槽骨骨缺损修复过程中,新生骨形成的速度、质量和长期稳定性与口腔种植义齿修复息息相关。自体骨或异体骨移植、屏障膜技术等传统的治疗策略,在修复牙槽骨缺损方面颇有成效。然而,新生骨组织仍然难以与原始骨相提并论。基因增强型骨组织工程策略因其高效、稳定的促进骨再生,而受到越来越多的关注。骨代谢作用主要通过全身或局部的生长因子的调控。作为众多成骨因子之中的一员,音猬因子(Sonic hedgehog,Shh)能够通过骨形成蛋白(BMP)及甲状旁腺激素蛋白(PTHrP)等信号通路诱导间充质干细胞向成骨细胞分化,并在骨再生修复过程中发挥着重要的作用。本研究拟通过基因增强型骨组织工程方法,利用Shh修饰的骨髓间充质干细胞与磷酸三钙骨移植材料复合于犬牙槽骨缺损模型中,评价Shh基因在牙槽骨缺损修复中的骨再生能力。方法是构建携带Shh基因的慢病毒载体,犬骨髓间充质干细胞常规分离培养后转导Shh慢病毒载体。荧光实时定量聚合酶链式反应、蛋白免疫印迹方法检测外源Shh基因的表达情况,并通过检测碱性磷酸酶活性及成骨相关因子的表达,体外评价Shh基因促骨髓间充质干细胞成骨分化的能力。继而将转基因细胞与β-磷酸三钙材料复合,体外检测三维培养条件对细胞生物学性状、胞内成骨因子水平的影响。最终将Shh基因增强型组织工程骨移植到犬下颌骨种植体周围骨缺损区,分别于术后4周和12周通过影像学及组织形态学方法观察Shh基因增强型组织工程骨对牙槽骨缺损修复的影响。研究结果显示,Shh基因能够有效地促进牙槽骨缺损区新骨形成及血管再生,组织形态学定量分析也证实Shh处理组的新骨形成显著高于其他对照组。本研究证明利用基因增强型骨组织工程原理将Shh基因传递到骨缺损区域能够显著的促进骨再生修复,进一步推进了Shh介导的基因增强型骨组织工程方法在骨再生研究中的发展。
Alveolar bone defects resulting from trauma, tumor, congenital deformities or serious periodontitis present a challenge to prosthetic reconstruction. The speed, quality and long-term stability of new bone formation in repair of alveolar bone defects are closely related to dental implantation. Autogenous bone, allograft bone, guided bone regeneration and other traditional methods for treatment of alveolar defects have achieved acceptable outcomes. However, the new generated bone can not be compared with the original bone. Gene-enhanced tissue engineering method as an alterative has attracted more and more attention. Bone metabolism is mainly mediated through local or systemic factors. Among these factors, Sonic hedgehog (Shh) is involved in osteoblast differentiation through BMP and PTHrP signal pathways, and may play an important role in bone formation. In this study, a gene-enhanced tissue-engineering approach was used to assess bone regenerative capacity of Sonic hedgehog (Shh) - transduced mesenchymal stem cells delivered to canine alveolar bone defects in beta-tricalcium phosphate (β-TCP) matrix. The lentiviral vector-mediated Shh gene (Lenti-Shh) was constructed in this study. Canine bone marrow-derived mesenchymal stem cells (MSCs) were transduced with the Lenti-Shh vector after routine isolation and culture in vitro. The exogenous Shh gene was assessed by the reverse transcriptase-polymerase chain reaction analysis and western blot detection. Osteogenic potential of Shh-transduced MSCs was evaluated in terms of the activity of alkaline phosphatase and the mRNA expression levels of osteogenic marker genes in vitro. Thereafter, the transduced MSCs were seeded on the biodegradableβ-TCP scaffold, and this composite was cultured in a three-dimensional culture system in vitro. The canine alveolar bone defects were surgically created following implant beds preparation in beagle dogs. Finally, the gene-enhanced tissue engineering bone was introduced into the alveolar defects around dental implants. The bone regenerative capacity of the gene-enhanced tissue engineering bone was assessed radiographically and histologically at 4 and 12 weeks postimplantation. The results showed that the increased bone formation accompanied with angiogenesis was induced by Shh transgene delivery in vivo. Quantitative analysis of histological sections confirmed statistically significant amounts of bone regeneration in Shh-enhanced groups compared to controls. Our study demonstrated that Shh gene delivery to bone defects, in this case through a gene-enhanced tissue-engineering approach, resulted in significant bone regeneration. This encourages further development of the Shh gene-enhanced tissue-engineering approach for bone regeneration.
Alveolar bone defects resulting from trauma, tumor, congenital deformities or serious periodontitis present a challenge to prosthetic reconstruction. The speed, quality and long-term stability of new bone formation in repair of alveolar bone defects are closely related to dental implantation. Autogenous bone, allograft bone, guided bone regeneration and other traditional methods for treatment of alveolar defects have achieved acceptable outcomes. However, the new generated bone can not be compared with the original bone. Gene-enhanced tissue engineering method as an alterative has attracted more and more attention. Bone metabolism is mainly mediated through local or systemic factors. Among these factors, Sonic hedgehog (Shh) is involved in osteoblast differentiation through BMP and PTHrP signal pathways, and may play an important role in bone formation. In this study, a gene-enhanced tissue-engineering approach was used to assess bone regenerative capacity of Sonic hedgehog (Shh) - transduced mesenchymal stem cells delivered to canine alveolar bone defects in beta-tricalcium phosphate (β-TCP) matrix. The lentiviral vector-mediated Shh gene (Lenti-Shh) was constructed in this study. Canine bone marrow-derived mesenchymal stem cells (MSCs) were transduced with the Lenti-Shh vector after routine isolation and culture in vitro. The exogenous Shh gene was assessed by the reverse transcriptase-polymerase chain reaction analysis and western blot detection. Osteogenic potential of Shh-transduced MSCs was evaluated in terms of the activity of alkaline phosphatase and the mRNA expression levels of osteogenic marker genes in vitro. Thereafter, the transduced MSCs were seeded on the biodegradableβ-TCP scaffold, and this composite was cultured in a three-dimensional culture system in vitro. The canine alveolar bone defects were surgically created following implant beds preparation in beagle dogs. Finally, the gene-enhanced tissue engineering bone was introduced into the alveolar defects around dental implants. The bone regenerative capacity of the gene-enhanced tissue engineering bone was assessed radiographically and histologically at 4 and 12 weeks postimplantation. The results showed that the increased bone formation accompanied with angiogenesis was induced by Shh transgene delivery in vivo. Quantitative analysis of histological sections confirmed statistically significant amounts of bone regeneration in Shh-enhanced groups compared to controls. Our study demonstrated that Shh gene delivery to bone defects, in this case through a gene-enhanced tissue-engineering approach, resulted in significant bone regeneration. This encourages further development of the Shh gene-enhanced tissue-engineering approach for bone regeneration.
引文
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