Aguilar Izath N, Trippel Stephen B, Shi Shuiliang, Bonassar Lawrence J
Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA ; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Cartilage. 2015 Oct;6(4):264-72. doi: 10.1177/1947603515578691.
The goal of this study was to compare the efficacy of endogenous upregulation of IGF-I by gene therapy and exogenous addition of insulin-like growth factor I (IGF-I) in enhancing proteoglycan synthesis by skeletally mature and neonatal chondrocytes. Chondrocyte transplantation therapy is a common treatment for focal cartilage lesions, with both mature and neonatal chondrocytes used as a cell source. Additionally, gene therapy strategies to upregulate growth factors such as IGF-I have been proposed to augment chondrocyte transplantation therapies.
Both skeletally mature and neonatal chondrocytes were exposed to either an adeno-associated virus-based plasmid containing the IGF-I gene or exogenous IGF-I.
Analysis of IGF-I and glycosaminoglycan production using a 4-parameter dose-response model established a clear connection between the amount of IGF-I produced by cells and their biosynthetic response. Both neonatal and mature chondrocytes showed this relationship, but the sensitivities were quite different, with EC50 of 0.57 ng/mL for neonatal chondrocytes and EC50 of 8.70 ng/mL IGF-I for skeletally mature chondrocytes.
These data suggest that IGF-I gene therapy may be more effective with younger cell sources. Both cell types were less sensitive to exogenous IGF-I than endogenous IGF-I.
本研究的目的是比较基因疗法内源性上调胰岛素样生长因子I（IGF-I）与外源性添加胰岛素样生长因子I（IGF-I）在促进骨骼成熟和新生软骨细胞蛋白聚糖合成方面的疗效。软骨细胞移植疗法是治疗局灶性软骨损伤的常用方法，成熟和新生软骨细胞均用作细胞来源。此外，已提出上调IGF-I等生长因子的基因治疗策略以增强软骨细胞移植疗法。
将骨骼成熟和新生软骨细胞分别暴露于含IGF-I基因的腺相关病毒载体质粒或外源性IGF-I。
使用四参数剂量反应模型对IGF-I和糖胺聚糖生成进行分析，确定了细胞产生的IGF-I量与其生物合成反应之间的明确联系。新生和成熟软骨细胞均显示出这种关系，但敏感性差异很大，新生软骨细胞的半数有效浓度（EC50）为0.57 ng/mL，骨骼成熟软骨细胞的IGF-I的EC50为8.70 ng/mL。
这些数据表明，IGF-I基因疗法对较年轻的细胞来源可能更有效。两种细胞类型对外源性IGF-I的敏感性均低于内源性IGF-I。
