Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo
Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo
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DOI：
10.1038/gt.2014.58
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发表时间：
2014-09-01
期刊：
影响因子：
5.1
通讯作者：
Madry, H.
中科院分区：
文献类型：
--
作者：
Cucchiarini, M.;Madry, H.
直接治疗性基因转移是治疗关节软骨缺损的一种很有前途的方法。在这里，我们测试了重组腺相关病毒（rAAV）胰岛素样生长因子I （IGF-I）载体在体内改善软骨病变早期修复的能力。与对照组（lacZ）和参与修复过程的细胞（间充质干细胞、软骨细胞）相比，将该载体应用于兔膝关节骨软骨缺损中3周。在处理过的病变和离体细胞中观察到高效的igf - 1表达。raav介导的IGF-I过表达能够刺激体外和体内的生物活性（增殖、基质合成）。体内igf - 1治疗耐受性良好，显示整个骨软骨单位的修复能力显著改善。IGF-I过表达延迟了新形成软骨的终末分化和肥大，可能是由于对RUNX2和β -catenin成骨表达的不同影响，以及该因子对该区域甲状旁腺激素/甲状旁腺激素相关蛋白通路的刺激作用。igf - 1的产生改善了缺损软骨下骨层的重建，显示该区域RUNX2表达水平升高。这些发现显示了直接应用治疗性raav治疗软骨病变的潜力。
Direct therapeutic gene transfer is a promising tool to treat articular cartilage defects. Here, we tested the ability of an recombinant adeno-associated virus (rAAV) insulin-like growth factor I (IGF-I) vector to improve the early repair of cartilage lesions in vivo. The vector was administered for 3 weeks in osteochondral defects created in the knee joints of rabbits compared with control (lacZ) treatment and in cells that participate in the repair processes (mesenchymal stem cells, chondrocytes). Efficient IGF-I expression was observed in the treated lesions and in isolated cells in vitro. rAAV-mediated IGF-I overexpression was capable of stimulating the biologic activities (proliferation, matrix synthesis) both in vitro and in vivo. IGF-I treatment in vivo was well tolerated, revealing significant improvements of the repair capabilities of the entire osteochondral unit. IGF-I overexpression delayed terminal differentiation and hypertrophy in the newly formed cartilage, possibly due to contrasting effects upon the osteogenic expression of RUNX2 and beta-catenin and to stimulating effects of this factor on the parathyroid hormone/parathyroid hormone-related protein pathway in this area. Production of IGF-I improved the reconstitution of the subchondral bone layer in the defects, showing increased RUNX2 expression levels in this zone. These findings show the potential of directly applying therapeutic rAAVs to treat cartilage lesions.