Systemic inhibition of canonical Notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing.
Systemic inhibition of canonical Notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing.
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DOI：
10.1371/journal.pone.0068726
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hankenson KD
中科院分区：
文献类型：
--
作者：
Dishowitz MI;Mutyaba PL;Takacs JD;Barr AM;Engiles JB;Ahn J;Hankenson KD
Notch信号通路是胚胎骨发育的重要调节因子，并且在骨修复期间再现了发育的许多方面。我们以前曾报道过Notch信号成分在骨折愈合过程中上调。然而，Notch通路在骨再生中的意义尚未被描述。因此，本研究的目的是通过使用时间控制的诱导型转基因小鼠模型（Mx 1-Cre;dnMAMLf/-）来损害RBPjκ介导的经典Notch信号传导，来确定Notch信号传导在调节骨折愈合中的重要性。Mx 1启动子被合成激活，导致双侧胫骨骨折发生前短暂调节系统性dnMAML表达。这使得小鼠能够经历未改变的胚胎学和出生后骨骼发育。结果显示，全身性Notch抑制延长了炎性细胞因子和中性粒细胞炎症的表达，并减少了骨折后10天（dpf）骨痂内软骨形成的比例。Notch抑制在10 dpf时不影响早期骨形成，但在20 dpf时显著改变了骨成熟和重塑。dnMAML骨折中骨体积分数增加，这是由于骨痂大小适度减少而骨量无变化，与骨小梁厚度增加但连接密度降低一致，表明骨模式发生改变。Notch抑制降低了总的成骨细胞密度，其由更多的骨细胞而不是成骨细胞组成。dnMAML也降低破骨细胞密度，表明破骨细胞活性对骨折愈合的改变也很重要。很可能全身性Notch抑制在细胞类型内具有直接作用，以及由骨折愈合级联中的时间上游事件引发的间接作用。令人惊讶的是，Notch抑制不改变细胞增殖。总之，我们的研究结果表明，Notch信号通路是成功的骨折愈合所需的事件的适当时间进展所必需的。
The Notch signaling pathway is an important regulator of embryological bone development, and many aspects of development are recapitulated during bone repair. We have previously reported that Notch signaling components are upregulated during bone fracture healing. However, the significance of the Notch pathway in bone regeneration has not been described. Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model (Mx1-Cre;dnMAMLf/-) to impair RBPjκ-mediated canonical Notch signaling. The Mx1 promoter was synthetically activated resulting in temporally regulated systemic dnMAML expression just prior to creation of bilateral tibial fractures. This allowed for mice to undergo unaltered embryological and post-natal skeletal development. Results showed that systemic Notch inhibition prolonged expression of inflammatory cytokines and neutrophil cell inflammation, and reduced the proportion of cartilage formation within the callus at 10 days-post-fracture (dpf) Notch inhibition did not affect early bone formation at 10dpf, but significantly altered bone maturation and remodeling at 20dpf. Increased bone volume fraction in dnMAML fractures, which was due to a moderate decrease in callus size with no change in bone mass, coincided with increased trabecular thickness but decreased connectivity density, indicating that patterning of bone was altered. Notch inhibition decreased total osteogenic cell density, which was comprised of more osteocytes rather than osteoblasts. dnMAML also decreased osteoclast density, suggesting that osteoclast activity may also be important for altered fracture healing. It is likely that systemic Notch inhibition had both direct effects within cell types as well as indirect effects initiated by temporally upstream events in the fracture healing cascade. Surprisingly, Notch inhibition did not alter cell proliferation. In conclusion, our results demonstrate that the Notch signaling pathway is required for the proper temporal progression of events required for successful bone fracture healing.
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影响因子：
2.8
作者：
Dishowitz, Michael I.;Terkhorn, Shawn P.;Hankenson, Kurt D.
通讯作者：
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