Hurtig Mark, Chubinskaya Susan, Dickey Jim, Rueger David
Department of Clinical Studies, University of Guelph, 50 McGilvray Lane, Guelph, ON, Canada, N1G 2W1.
J Orthop Res. 2009 May;27(5):602-11. doi: 10.1002/jor.20787.
In vivo studies were used to characterize a model of cartilage injury leading to osteoarthritis progression in the medial femorotibial joint of sheep. In three subsequent studies, bilateral impact injuries were created and one joint received intraarticular injections of 340 microg of rhBMP-7 protein in a collagen particle carrier while the contralateral knee received the vehicle alone. Sheep were allocated to three groups that received intraarticular injections on day 0 (group A), 21 (group B), or 90 (group C) after experimental knee injury. In each group the, joints were evaluated for signs of osteoarthritis progression 90 days after the last treatment using India ink stained area, OARSI histological scoring, cartilage sGAG content, immunostaining for apoptosis (TUNEL), caspase-3, collagen degradation (Col 2 3/4C short collagen epitope), and the endogenous (pro-) form of BMP-7 protein. Knee joints that received rhBMP-7 immediately after injury had small focal lesions at the injury site that did not progress into the surrounding cartilage. Joints that received BMP-7 3 weeks after injury were improved and had limited progression compared to controls, but joints that received the protein 12 weeks after injury had no statistically significant improvement. These studies suggest that BMP-7 may be chondroprotective after traumatic injury in patients if it is administered within 3 to 4 weeks of the index injury. The mechanism of protection after sublethal injury appeared to be an increased survival of chondrocytes that are able to participate in the repair process.
体内研究用于表征绵羊股胫内侧关节软骨损伤导致骨关节炎进展的模型。在随后的三项研究中，制造双侧撞击损伤，一个关节接受在胶原颗粒载体中注射340微克重组人骨形态发生蛋白-7（rhBMP-7）蛋白，而对侧膝关节仅接受载体。绵羊被分为三组，分别在实验性膝关节损伤后第0天（A组）、第21天（B组）或第90天（C组）接受关节内注射。在每组中，在最后一次治疗后90天，使用印度墨水染色面积、骨关节炎研究学会国际分会（OARSI）组织学评分、软骨硫酸糖胺聚糖（sGAG）含量、凋亡免疫染色（TUNEL）、半胱天冬酶-3、胶原降解（Col 2 3/4C短胶原表位）以及内源性（前体）形式的BMP-7蛋白对关节进行骨关节炎进展迹象评估。损伤后立即接受rhBMP-7的膝关节在损伤部位有小的局灶性病变，未进展至周围软骨。与对照组相比，损伤后3周接受BMP-7的关节有所改善且进展有限，但损伤后12周接受该蛋白的关节无统计学上的显著改善。这些研究表明，如果在初次损伤后3至4周内给药，BMP-7对创伤性损伤患者可能具有软骨保护作用。亚致死性损伤后的保护机制似乎是能够参与修复过程的软骨细胞存活率增加。
