Activation of Wnt Signaling by Mechanical Loading Is Impaired in the Bone of Old Mice.
Activation of Wnt Signaling by Mechanical Loading Is Impaired in the Bone of Old Mice.
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DOI：
10.1002/jbmr.2900
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发表时间：
2016-12
期刊：
影响因子：
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通讯作者：
Silva MJ
中科院分区：
文献类型：
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作者：
Holguin N;Brodt MD;Silva MJ
衰老减少了由机械负荷引起的骨形成，但这种损伤的机制仍不清楚。由于Wnt信号传导是最佳负荷诱导骨形成所必需的，我们假设衰老损害了负荷诱导的Wnt信号传导激活。我们分析了5月龄、12月龄和22月龄的C57 Bl/6 JN小鼠的动态组织形态计量学，这些小鼠经历了多天的胫骨压缩，并证实了第5天骨膜负荷反应的年龄相关性下降。类似地，1天的负荷增加了成年（5个月大）小鼠的骨膜和皮质内骨形成，但老年（22个月大）小鼠没有反应。这些发现证实了与骨形成相关的基因的mRNA表达和加载后胫骨中的Wnt通路。多次（3至5天）加载上调的骨形成相关基因，例如，Osx和Col 1a 1，但年龄较大的小鼠的反应明显较低。在所有小鼠中，Wnt负调控因子Sost和Dkk 1的表达在一天的负荷下被抑制，但仅在成年小鼠中持续抑制。此外，多天的负荷反复抑制Sost和Dkk 1在成年人，但不是在旧胫骨。通过对TOPGAL小鼠胫骨中的硬化蛋白和LacZ进行骨细胞染色，进一步评估对负荷的年龄依赖性反应。在1天的负荷后，在5月龄和12月龄的小鼠中，硬化蛋白阳性的骨细胞较少，并且确证性地，更多的骨细胞是LacZ阳性（Wnt活性）。然而，尽管这些变化在5个月大的小鼠中持续了多天的负荷，但在12个月大的小鼠中却没有持续。最后，Wnt 1和Wnt 7 b是19个Wnt配体中最具负荷响应性的。然而，在单次负荷后4小时，尽管它们的表达在成年小鼠中上调了3倍至10倍，但在老年小鼠中没有改变。总之，老年小鼠对负荷的骨形成反应降低可能是由于重复负荷不能维持Wnt活性。
Aging diminishes bone formation engendered by mechanical loads, but the mechanism for this impairment remains unclear. Because Wnt signaling is required for optimal loading-induced bone formation, we hypothesized that aging impairs the load-induced activation of Wnt signaling. We analyzed dynamic histomorphometry of 5-month-old, 12-month-old, and 22-month-old C57Bl/6JN mice subjected to multiple days of tibial compression and corroborated an age-related decline in the periosteal loading response on day 5. Similarly, 1 day of loading increased periosteal and endocortical bone formation in young-adult (5-month-old) mice, but old (22-month-old) mice were unresponsive. These findings corroborated mRNA expression of genes related to bone formation and the Wnt pathway in tibias after loading. Multiple bouts (3 to 5 days) of loading upregulated bone formation–related genes, e.g., Osx and Col1a1, but older mice were significantly less responsive. Expression of Wnt negative regulators, Sost and Dkk1, was suppressed with a single day of loading in all mice, but suppression was sustained only in young-adult mice. Moreover, multiple days of loading repeatedly suppressed Sost and Dkk1 in young-adult, but not in old tibias. The age-dependent response to loading was further assessed by osteocyte staining for Sclerostin and LacZ in tibia of TOPGAL mice. After 1 day of loading, fewer osteocytes were Sclerostin-positive and, corroboratively, more osteocytes were LacZ-positive (Wnt active) in both 5-month-old and 12-month-old mice. However, although these changes were sustained after multiple days of loading in 5-month-old mice, they were not sustained in 12-month-old mice. Last, Wnt1 and Wnt7b were the most load-responsive of the 19 Wnt ligands. However, 4 hours after a single bout of loading, although their expression was upregulated threefold to 10-fold in young-adult mice, it was not altered in old mice. In conclusion, the reduced bone formation response of aged mice to loading may be due to failure to sustain Wnt activity with repeated loading.