Bone marrow fibrosis with fibrocytic and immunoregulatory responses induced by β-catenin activation in osteoprogenitors.
Bone marrow fibrosis with fibrocytic and immunoregulatory responses induced by β-catenin activation in osteoprogenitors.
复制标题
DOI：
10.1016/j.bone.2015.12.003
复制
发表时间：
2016-03
期刊：
影响因子：
4.1
通讯作者：
Jian Yu;Jingjing Cao;Hanjun Li;Pei Liu;Shuqin Xu;Rujiang Zhou;Zhengju Yao;Xizhi Guo
中科院分区：
文献类型：
--
作者：
Jian Yu;Jingjing Cao;Hanjun Li;Pei Liu;Shuqin Xu;Rujiang Zhou;Zhengju Yao;Xizhi Guo
Wnt/β-Catenin信号转导通路在骨纤维异常增殖症的发生中起重要作用。然而，目前尚不清楚纤维细胞和免疫细胞是否参与了β-连环蛋白介导的骨髓纤维化。在这项研究中，我们发现β-catenin被Col1a1-Cre(3.6kb)的结构性激活表现为骨髓纤维化，其特征是纤维细胞、肌成纤维细胞和骨祖细胞的数量增加。谱系追踪和免疫组化检测表明，Col3.6-Crek不仅在骨祖细胞中显示Cre重组酶活性，而且在骨内壁龛中的单核细胞来源的纤维细胞中也显示出Cre重组酶活性。此外，β-catenin还可刺激骨髓细胞分泌细胞因子和促纤维化信号，包括GM-β、转化生长因子-1和血管内皮生长因子。因此，在突变的骨髓中，分化的未成熟单核细胞来源的树突状细胞和幼稚T细胞的频率显著增加。这些表型与COL1a1-Cre(2.3kb)驱动的成熟成骨细胞中β-连环蛋白激活后的表型有很大不同。我们的研究结果提示，β-连环蛋白介导的骨髓纤维化可能与转化生长因子-β-1促进的纤维细胞活化和免疫调节反应有关。这项研究可能会为理解和发展骨纤维异常增生症的治疗策略提供新的线索。
Wnt/β-catenin signaling has been reported to contribute to the development of bone fibrous dysplasia. However, it remains unclear whether fibrocytes and immune cells are involved in this β-catenin-mediated bone marrow fibrosis. In this study, we showed that constitutive activation of β-catenin byCol1a1-Cre(3.6-kb) exhibited bone marrow fibrosis, featured with expanded populations of fibrocytes, myofibroblasts and osteoprogenitors. Lineage tracing and IHC examinations showed thatCol3.6-Credisplay Cre recombinase activity not only in osteoprogenitors, but also in monocyte-derived fibrocytes in the endosteal niches of bones. Additionally, β-catenin stimulated the secretion of cytokines and pro-fibrotic signals in bone marrow, including GM-CSF, TGFβ1 and VEGF. Consequently, the frequency of differentiated immature monocyte-derived dendritic cells and naïve T cells was markedly increased in the mutant bone marrow. These phenotypes were quite different from those following β-catenin activation in mature osteoblasts driven byCol1a1-Cre(2.3-kb). Our findings suggested that a conserved pro-fibrotic signal cascade might underlie β-catenin-mediated bone marrow fibrosis, involving TGFβ1-enhanced fibrocyte activation and immunoregulatory responses. This study might shed new light on the understanding and development of a therapeutic strategy for bone fibrous dysplasia.