Department of Zoology, School of Natural Sciences, Trinity College Dublin, Ireland.
Bone. 2010 May;46(5):1275-85. doi: 10.1016/j.bone.2009.11.026. Epub 2009 Nov 27.
Mechanical forces are essential for normal adult bone function and repair, but the impact of prenatal muscle contractions on bone development remains to be explored in depth in mammalian model systems. In this study, we analyze skeletogenesis in two 'muscleless' mouse mutant models in which the formation of skeletal muscle development is disrupted; Myf5(nlacZ/nlacZ):MyoD(-/-) and Pax3(Sp/Sp) (Splotch). Ossification centers were found to be differentially affected in the muscleless limbs, with significant decreases in bone formation in the scapula, humerus, ulna and femur, but not in the tibia. In the scapula and humerus, the morphologies of ossification centers were abnormal in muscleless limbs. Histology of the humerus revealed a decreased extent of the hypertrophic zone in mutant limbs but no change in the shape of this region. The elbow joint was also found to be clearly affected with a dramatic reduction in the joint line, while no abnormalities were evident in the knee. The humeral deltoid tuberosity was significantly reduced in size in the Myf5(nlacZ/nlacZ):MyoD(-/-) mutants while a change in shape but not in size was found in the humeral tuberosities of the Pax3(Sp/Sp) mutants. We also examined skeletal development in a 'reduced muscle' model, the Myf5(nlacZ/+):MyoD(-/-) mutant, in which skeletal muscle forms but with reduced muscle mass. The reduced muscle phenotype appeared to have an intermediate effect on skeletal development, with reduced bone formation in the scapula and humerus compared to controls, but not in other rudiments. In summary, we have demonstrated that skeletal development is differentially affected by the lack of skeletal muscle, with certain rudiments and joints being more severely affected than others. These findings indicate that the response of skeletal progenitor cells to biophysical stimuli may depend upon their location in the embryonic limb, implying a complex interaction between mechanical forces and location-specific regulatory factors affecting bone and joint development.
机械力对于成人骨骼的正常功能和修复至关重要，但在哺乳动物模型系统中，产前肌肉收缩对骨骼发育的影响仍有待深入研究。在这项研究中，我们分析了两种“无肌肉”小鼠突变模型中的骨骼生成，这两种模型中骨骼肌肉发育的形成受到了破坏；Myf5(nlacZ/nlacZ):MyoD(-/-) 和 Pax3(Sp/Sp) (Splotch)。发现无肌肉肢体的骨化中心受到不同程度的影响，肩胛骨、肱骨、尺骨和股骨的骨形成显著减少，但胫骨不受影响。在肩胛骨和肱骨中，无肌肉肢体的骨化中心形态异常。肱骨组织学显示突变肢体的肥大区范围减小，但该区域的形状没有变化。还发现肘关节明显受到影响，关节线明显缩小，而膝关节没有异常。Myf5(nlacZ/nlacZ):MyoD(-/-) 突变体的肱骨三角肌粗隆明显减小，而 Pax3(Sp/Sp) 突变体的肱骨粗隆则发生了形状改变但大小未变。我们还检查了“肌肉减少”模型，即 Myf5(nlacZ/+):MyoD(-/-) 突变体中的骨骼发育，其中形成了骨骼肌，但肌肉质量减少。与对照组相比，减少的肌肉表型似乎对骨骼发育有中等影响，肩胛骨和肱骨的骨形成减少，但其他原始骨骼没有。总之，我们已经证明，骨骼发育受到缺乏骨骼肌的不同影响，某些原始骨骼和关节受到的影响比其他关节更严重。这些发现表明，骨骼祖细胞对生物物理刺激的反应可能取决于它们在胚胎肢体中的位置，这意味着机械力和位置特异性调节因子之间存在复杂的相互作用，影响骨骼和关节的发育。
