It has been known that moderate mechanical loading, like that caused by exercise, promotes bone formation. However, its underlying mechanisms remain elusive. Here we showed that moderate running dramatically improved trabecular bone in mice tibias with an increase in bone volume fraction and trabecular number and a decrease in trabecular pattern factor. Results of immunohistochemical and histochemical staining revealed that moderate running mainly increased the number of osteoblasts but had no effect on osteoclasts. In addition, we observed a dramatic increase in the number of colony forming unit-fibroblast in endosteal bone marrow and the percentage of CD45⁻Leptin receptor⁺ (CD45⁻LepR⁺) endosteal mesenchymal progenitors. Bioinformatics analysis of the transcriptional data from gene expression omnibus (GEO) database identified chemokine c-c-motif ligands (CCL2) as a critical candidate induced by mechanical loading. Interestingly, we found that CCL2 was up-regulated mainly in osteoblastic cells in the tibia of mice after moderate running. Further, we found that mechanical loading up-regulated the expression of CCL2 by activating ERK1/2 pathway, thereby stimulating migration of endosteal progenitors. Finally, neutralizing CCL2 abolished the recruitment of endosteal progenitors and the increased bone formation in mice after 4 weeks running. These results therefore uncover an unknown connection between osteoblasts and endosteal progenitors recruited in the increased bone formation induced by mechanical loading.

中文翻译：

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CCL2是成骨细胞和骨间充质基质细胞之间串扰的关键机械响应介质

众所周知，适度的机械负荷，如运动引起的负荷，可促进骨骼形成。然而，其潜在机制仍然难以捉摸。在这里，我们表明适度跑步显着改善了小鼠胫骨的骨小梁，增加了骨体积分数和骨小梁数量，并降低了骨小梁模式因子。免疫组化和组织化学染色结果显示，适度跑步主要增加成骨细胞数量，但对破骨细胞没有影响。此外，我们观察到集落的数目急剧增加形成骨内膜骨髓单元成纤维细胞和CD45的百分比^-瘦素受体⁺（CD45 ^-瘦素受体⁺) 骨内膜间充质祖细胞。来自基因表达综合 (GEO) 数据库的转录数据的生物信息学分析将趋化因子 cc 基序配体 (CCL2) 确定为机械加载诱导的关键候选物。有趣的是，我们发现 CCL2 在适度跑步后主要在小鼠胫骨的成骨细胞中上调。此外，我们发现机械负荷通过激活 ERK1/2 通路上调 CCL2 的表达，从而刺激骨内膜祖细胞的迁移。最后，在运行 4 周后，中和 CCL2 消除了小鼠骨内膜祖细胞的募集和骨形成的增加。因此，这些结果揭示了成骨细胞和在机械负荷诱导的骨形成增加中募集的骨内膜祖细胞之间的未知联系。