MCP1 triggers monocyte dysfunctions during abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis.
MCP1 triggers monocyte dysfunctions during abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis.
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MCP1 在强直性脊柱炎间充质干细胞异常成骨分化过程中触发单核细胞功能障碍。
DOI：
10.1007/s00109-016-1489-x
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Shen Huiyong
中科院分区：
文献类型：
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作者：
Xie Zhongyu;Wang Peng;Li Jinteng;Li Yuxi;Wang Shan;Wu Xiaohua;Sun Suhe;Cen Shuizhong;Su Hongjun;Deng Wen;Liu Zhenhua;Ouyang Yi;Wu Yanfeng;Shen Huiyong
强直性脊柱炎（Ankylosing Spondylitis，AS）是一种以病理性成骨和炎症为特征的慢性炎症性疾病.然而，AS的发病机制以及这种疾病中骨生成和炎症之间的病理关系仍然很大程度上未知。间充质干细胞（Mesenchymal stem cells，MSCs）是具有成骨分化和免疫调节功能的多能祖细胞。最近，我们证明，从AS患者（ASMSC）的骨髓间充质干细胞比健康供体（HDMSCs），因此似乎是AS的病理性成骨分化的一个组成部分有更大的潜力成骨分化。先前的研究表明，MSC的免疫调节能力随着分化而改变。然而，ASMSCs在异常成骨分化过程中的后续作用尚不清楚。在此，我们进一步证明了ASMSCs在成骨分化过程中比HDMSCs分泌更多的单核细胞趋化蛋白1（MCP 1）。这种MCP 1分泌的增强增强了单核细胞的迁移，增加了经典的巨噬细胞极化，并增强了TNF-α的分泌。使用编码短发夹RNA的慢病毒抑制成骨分化的ASMSC分泌MCP 1改善了这些功能障碍。用U 0126阻断ASMSCs中的ERK 1/2通路可纠正异常的成骨分化，抑制MCP 1过表达，并防止随后的单核细胞功能障碍。最后，MCP 1的表达在体内ASMSCs成骨分化过程中上调，并在AS患者骨化部位的成骨细胞中局部增强。总之，我们的研究确定，MCP 1过度表达在异常成骨分化的ASMSC触发单核细胞功能障碍。我们提出了一个新的假说，即病理性成骨可以导致AS的炎症反应。这一假说可能有助于揭示骨免疫学领域中成骨与炎症之间的确切病理关系。关键信息ASMSCs在异常成骨分化过程中分泌更多的MCP 1，MCP 1过表达导致单核细胞功能障碍，AS中病理性成骨可导致炎症。
AbstractAnkylosing spondylitis (AS) is a chronic inflammatory disease characterized by pathological osteogenesis and inflammation. However, the pathogenesis of AS and the pathological relationship between osteogenesis and inflammation in this disease remain largely unknown. Mesenchymal stem cells (MSCs) are multipotent progenitor cells capable of osteogenic differentiation and immunoregulation. Recently, we demonstrated that MSCs from AS patients (ASMSCs) have a greater potential for osteogenic differentiation than MSCs from healthy donors (HDMSCs), which therefore seems to be a component of pathological osteogenesis in AS. Previous studies have indicated that the immunoregulatory abilities of MSCs change following differentiation. However, the subsequent effects of ASMSCs during abnormal osteogenic differentiation are unclear. Here, we further demonstrated that ASMSCs secreted more monocyte chemoattractant protein 1 (MCP1) than HDMSCs during osteogenic differentiation. This enhanced MCP1 secretion augmented monocyte migration, increased classical macrophage polarization, and enhanced TNF-α secretion. Inhibiting MCP1 secretion from osteogenic differentiated ASMSCs using lentiviruses encoding short hairpin RNAs ameliorated these dysfunctions. Blocking the ERK1/2 pathway in ASMSCs with U0126 corrected the abnormal osteogenic differentiation, inhibited MCP1 overexpression, and prevented subsequent monocyte dysfunction. Finally, MCP1 expression was up-regulated during osteogenic differentiation in ASMSCs in vivo and was locally augmented in osteoblasts at ossification sites in AS patients. In summary, our study determined that MCP1 overexpression during abnormal osteogenic differentiation of ASMSCs triggers monocyte dysfunctions. We propose the novel hypothesis that pathological osteogenesis can lead to inflammation in AS. This hypothesis may contribute to reveal the precise pathological relationship between osteogenesis and inflammation in the field of osteoimmunology.Key messageASMSCs secreted more MCP1 during abnormal osteogenic differentiation.MCP1 overexpression leads to monocyte dysfunctions.Pathological osteogenesis can lead to inflammation in AS.