Anderson Brian C, Christiansen Stephen P, McLoon Linda K
Department of Ophthalmology, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA.
Invest Ophthalmol Vis Sci. 2008 Jan;49(1):221-9. doi: 10.1167/iovs.07-0600.
Future pharmacologic treatment of strabismus may be optimized if drugs that are less potentially toxic to patients can be developed. Prior studies have shown that direct injection of extraocular muscles (EOMs) with insulin growth factor or fibroblast growth factor results in significant increases in the generation of EOM force. The purpose of this study was to examine the morphometric and physiological effects of direct EOM injection with the growth factors BMP4, TGFbeta1, Shh, and Wnt3A.
One superior rectus muscle of normal adult rabbits was injected with BMP4, TGFbeta1, Shh, or Wnt3A. The contralateral muscle was injected with an equal volume of saline to serve as a control. After 1 week, the animals were euthanatized, and both superior rectus muscles were removed and assayed physiologically. The muscles were stimulated at increasing frequencies to determine force generation. A separate group of treated and control superior rectus muscles were examined histologically for alterations in total muscle cross-sectional area and myosin heavy chain isoform (MyHC) composition.
One week after a single injection of BMP4, TGFbeta1, Shh, or Wnt3A, all treated muscles showed significant decreases in generation of force compared with control muscles. BMP4, TGFbeta1, Shh, and Wnt3A significantly decreased the mean myofiber cross-sectional area of fast MyHC-positive myofibers. BMP4 resulted in a conversion of fast-to-slow myofibers and a significant decrease in the percentage of developmental and neonatal MyHC-positive myofibers. Alterations in mean cross-sectional area and proportion of MyHCs were seen after injection with TGFbeta1, Shh, and Wnt3A. TGFbeta1 and BMP4 injections resulted in increased Pax7-positive satellite cells, whereas BMP4, TGFbeta1, and Wnt3A resulted in a decrease in MyoD-positive satellite cells.
These results suggest that, rather than using toxins or immunotoxins, a more biological approach to decrease muscle strength is possible and demonstrate the potential utility of myogenic signaling factors for decreasing EOM strength. Ongoing drug-delivery studies will elucidate means of extending treatment effect to make such agents clinically useful.
如果能够研发出对患者潜在毒性较小的药物，未来斜视的药物治疗可能会得到优化。先前的研究表明，向眼外肌（EOMs）直接注射胰岛素生长因子或成纤维细胞生长因子会导致EOM力量产生显著增加。本研究的目的是检查向EOM直接注射骨形态发生蛋白4（BMP4）、转化生长因子β1（TGFβ1）、音猬因子（Shh）和Wnt3A生长因子后的形态计量学和生理学效应。
向正常成年兔的一条上直肌注射BMP4、TGFβ1、Shh或Wnt3A。对侧肌肉注射等量生理盐水作为对照。1周后，对动物实施安乐死，取出双侧上直肌并进行生理学检测。以递增频率刺激肌肉以测定力量产生情况。另外取一组经处理和对照的上直肌进行组织学检查，以观察总肌肉横截面积和肌球蛋白重链异构体（MyHC）组成的变化。
单次注射BMP4、TGFβ1、Shh或Wnt3A 1周后，与对照肌肉相比，所有处理过的肌肉力量产生均显著下降。BMP4、TGFβ1、Shh和Wnt3A显著降低了快速MyHC阳性肌纤维的平均肌纤维横截面积。BMP4导致快速肌纤维向慢速肌纤维转化，发育性和新生MyHC阳性肌纤维的百分比显著降低。注射TGFβ1、Shh和Wnt3A后可见平均横截面积和MyHC比例的改变。注射TGFβ1和BMP4导致Pax7阳性卫星细胞增加，而BMP4、TGFβ1和Wnt3A导致MyoD阳性卫星细胞减少。
这些结果表明，降低肌肉力量的更具生物学特性的方法是可行的，即无需使用毒素或免疫毒素，并证明了肌源性信号因子在降低EOM力量方面的潜在效用。正在进行的药物递送研究将阐明延长治疗效果以使此类药物具有临床实用性的方法。
