Shen Hsain-Chung, Peng Hairong, Usas Arvydas, Gearhart Brian, Fu Freddie H, Huard Johnny
Growth and Development Laboratory, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213-2583, USA.
J Gene Med. 2004 Sep;6(9):984-91. doi: 10.1002/jgm.588.
Our previous studies have shown that muscle-derived cells, including a population of muscle stem cells, transduced with a retroviral vector expressing bone morphogenetic protein 4 (BMP4) can improve the healing of critical-size calvarial defects. However, we did not evaluate the functionality of the healed bone. The purpose of this study was to determine whether primary muscle-derived cells transduced with retroBMP4 can heal a long bone defect both structurally and functionally.
Primary muscle-derived cells were genetically engineered to express BMP4 and were implanted into 7-mm femoral defects created in syngeneic rats. Muscle-derived cells transduced with retroLacZ were used in the control group. Bone healing was monitored by radiography, histology, and biomechanical testing at designated time points.
Most of the defects treated with muscle-derived cells expressing BMP4 formed bridging callous by 6 weeks after surgery, and exhibited radiographically evident union at 12 weeks after cell implantation. Histological analysis at 12 weeks revealed that the medullary canal of the femur was restored and the cortex was remodeled between the proximal and distal ends of each BMP4-treated defect. In contrast, the defects treated with muscle-derived cells expressing beta-galactosidase displayed nonunion at all tested time points. An evaluation of the maximum torque-to-failure in the treatment group indicated that the healed bones possessed 77 +/- 28% of the strength of the contralateral intact femora. Torsional stiffness and energy-to-failure were not significantly different between the treated and intact limbs.
This study demonstrated that primary muscle-derived cells transduced with retroBMP4 can elicit both structural and functional healing of critical-size segmental long bone defects created in rats.
我们之前的研究表明，用表达骨形态发生蛋白4（BMP4）的逆转录病毒载体转导的肌肉来源细胞，包括一群肌肉干细胞，可改善临界大小颅骨缺损的愈合。然而，我们并未评估愈合骨的功能。本研究的目的是确定用逆转录BMP4转导的原代肌肉来源细胞能否在结构和功能上愈合长骨缺损。
对原代肌肉来源细胞进行基因工程改造以表达BMP4，并将其植入同基因大鼠制造的7毫米股骨缺损处。用逆转录LacZ转导的肌肉来源细胞用于对照组。在指定时间点通过放射照相、组织学和生物力学测试监测骨愈合情况。
大多数用表达BMP4的肌肉来源细胞治疗的缺损在术后6周形成桥接骨痂，并在细胞植入后12周在放射照片上显示明显愈合。12周时的组织学分析显示，股骨的髓腔得以恢复，并且在每个经BMP4治疗的缺损的近端和远端之间皮质得到重塑。相比之下，用表达β-半乳糖苷酶的肌肉来源细胞治疗的缺损在所有测试时间点均显示未愈合。对治疗组最大破坏扭矩的评估表明，愈合骨的强度为对侧完整股骨的77±28%。治疗肢体和完整肢体之间的扭转刚度和破坏能量无显著差异。
本研究表明，用逆转录BMP4转导的原代肌肉来源细胞可引起大鼠临界大小节段性长骨缺损的结构和功能愈合。
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