Musculo-skeletal regeneration during distracionosteogenesis

牵张成骨是研究骨在体内对机械拉应力反应的一种有效方法。利用这种技术，我们在这里展示了骨对机械应力的独特反应，特别是骨激活素和MMP-3表达之间的关系。胫骨截骨术后1周（滞后期），将小鼠分为牵张成骨组和不牵张对照组。第一组胫骨延长2周（牵张期），随后延长5周（巩固期）。术后1周，主要表达骨激活素的成纤维细胞样细胞（可能是成骨细胞或软骨细胞的祖细胞）浸润到截骨部位。有趣的是，骨活化素和mmp -3双阳性成纤维细胞样细胞在牵张期在胫骨中积累。与免疫组化分析一致，牵张成骨组骨激活素和MMP-3转录本水平在牵张成骨组中分别显著升高，而在非牵张成骨组中未观察到MMP-3表达上调。为了阐明MMP-3表达的差异，我们检测了牵张期骨激活素的脱落。牵张成骨组产生骨激活素细胞外和细胞内碎片，而非牵张成骨组几乎没有检测到。这些发现表明骨活化素的脱落是MMP-3在延长节段表达上调的必要条件。最后，为了解决骨激活素介导的MMP-3在骨中的表达作用，我们将骨激活素转基因小鼠进行了该模型。在骨活素转基因小鼠中，与野生型小鼠相比，重塑区的骨吸收明显受到抑制，而骨形成没有改变。我们得出结论，骨活化素的脱落作为成纤维细胞样细胞的机械张力应力应答诱导剂，并介导对延长节段分散的愈伤组织吸收的抑制。少

Distraction osteogenesis is a useful technique to study the response of bone to mechanical tension-stress in vivo. Using this technique, we here showed the unique response of bone to mechanical stress, especially the association between osteoactivin and MMP-3 expression. At 1 week after osteotomy of tibiae (the lag phase), mice were divided into two groups : the distraction osteogenesis group and non-distraction control group. In the first group, the tibiae were lengthened for 2 weeks (the distraction phase), followed by sustaining the length for 5 weeks (the consolidation phase). At 1 week after surgery, fibroblast-like cells (possible progenitors of osteoblasts or chondrocytes), which mainly expressed osteoactivin, were infiltrated into the osteotomy site. Interestingly, osteoactivin- and MMP-3-double positive fibroblast-like cells were accumulated in tibiae during the distraction phase. Consistent with immunohistochemical analysis, the levels of osteoactivin and MMP-3 transcripts in … More tibiae were significantly increased by osteotomy and distraction, respectively, in the distraction osteogenesis group, whereas no upregulated expression of MMP-3 was observed in the non-distraction group. To elucidate this difference in MMP-3 expression, we examined the shedding of osteoactivin during the distraction phase. Extracellular and intracellular fragments of osteoactivin were produced in distraction osteogenesis group, while they were hardly detected in the non-distraction group. These findings suggest that the shedding of osteoactivin is necessary for upregulation of MMP-3 expression in the lengthened segment. Finally, to address the role of osteoactivin-mediated MMP-3 expression in bone, osteoactivin-transgenic mice were subjected to this model. In osteoactivin-transgenic mice, bone resorption in the remodeling zone was significantly inhibited, compared with wild-type mice, whereas bone formation was not altered. We conclude that the shedding of osteoactivin functions as a mechanical tension-stress respondent inducer of MMP-3 for the fibroblast-like cells, and it mediates the inhibition of distracted callus resorption in the lengthened segment. Less