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 by Col1a1-Cre (3.6-kb) exhibited bone marrow fibrosis, featured with expanded populations of fibrocytes, myofibroblasts and osteoprogenitors. Lineage tracing and IHC examinations showed that Col3.6-Cre display 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 by Col1a1-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.

中文翻译：

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骨祖细胞中 β-连环蛋白激活诱导的具有纤维细胞和免疫调节反应的骨髓纤维化

据报道，Wnt/β-catenin 信号传导有助于骨纤维发育不良的发展。然而，目前尚不清楚纤维细胞和免疫细胞是否参与了这种 β-连环蛋白介导的骨髓纤维化。在这项研究中，我们发现 Col1a1-Cre (3.6-kb) 对 β-catenin 的组成性激活表现出骨髓纤维化，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 IHC 检查显示 Col3.6-Cre 不仅在骨祖细胞中显示 Cre 重组酶活性，而且在骨的骨内壁龛中的单核细胞衍生的纤维细胞中也显示出Cre 重组酶活性。此外，β-连环蛋白刺激骨髓中细胞因子和促纤维化信号的分泌，包括 GM-CSF、TGFβ1 和 VEGF。最后，在突变的骨髓中，分化的未成熟单核细胞衍生的树突细胞和幼稚 T 细胞的频率显着增加。这些表型与由 Col1a1-Cre (2.3-kb) 驱动的成熟成骨细胞中 β-连环蛋白激活后的表型完全不同。我们的研究结果表明，保守的促纤维化信号级联可能是 β-连环蛋白介导的骨髓纤维化的基础，涉及 TGFβ1 增强的纤维细胞活化和免疫调节反应。这项研究可能会为理解和开发骨纤维发育不良的治疗策略提供新的思路。我们的研究结果表明，保守的促纤维化信号级联可能是 β-连环蛋白介导的骨髓纤维化的基础，涉及 TGFβ1 增强的纤维细胞活化和免疫调节反应。这项研究可能会为理解和开发骨纤维发育不良的治疗策略提供新的思路。我们的研究结果表明，保守的促纤维化信号级联可能是 β-连环蛋白介导的骨髓纤维化的基础，涉及 TGFβ1 增强的纤维细胞活化和免疫调节反应。这项研究可能会为理解和开发骨纤维发育不良的治疗策略提供新的思路。