DKK-1 and Its Influences on Bone Destruction: A Comparative Study in Collagen-Induced Arthritis Mice and Rheumatoid Arthritis Patients
DKK-1 and Its Influences on Bone Destruction: A Comparative Study in Collagen-Induced Arthritis Mice and Rheumatoid Arthritis Patients
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DOI：
10.1007/s10753-023-01898-z
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发表时间：
2023-09-09
期刊：
影响因子：
5.1
通讯作者：
Li，Juan
中科院分区：
文献类型：
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作者：
Zhao，Di;Wu，Lisheng;Li，Juan
Dickkopf-1（DKK-1）被认为是骨重建的主要调节因子。髓源性抑制细胞（MDSCs）作为破骨细胞（OCs）的前体细胞，参与了类风湿关节炎（RA）的骨破坏过程。然而，DKK-1和MDSC在RA中的作用尚未完全了解。我们研究了在RA患者和胶原诱导的关节炎（CIA）小鼠模型中，DKK-1水平与MDSC在不同组织和关节破坏中的表达之间的相关性。此外，CIA小鼠被给予重组DKK-1蛋白。检测各组大鼠关节炎评分、骨破坏情况、外周血和脾脏中MDSCs的百分比，并在体外用重组蛋白和DKK-1抑制剂干预MDSCs向OCs分化。观察OCs分化的数量及Wnt/β-catenin信号通路蛋白的表达。DKK-1水平与RA患者和CIA小鼠中MDSC和骨质侵蚀的频率呈正相关。体外实验表明，重组DKK-1可促进CIA小鼠骨髓间充质干细胞向OC分化，降低β-catenin和TCF 4的表达，增加CyclinD 1的表达。相反，DKK-1抑制剂具有相反的效果。我们的研究结果表明DKK-1通过靶向Wnt/β-catenin通路促进RA中MDSCs的扩增并促进MDSCs向OC的分化，加重RA的骨破坏。
Dickkopf-1 (DKK-1) has been considered a master regulator of bone remodeling. As precursors of osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs) were previously shown to participate in the process of bone destruction in rheumatoid arthritis (RA). However, the role of DKK-1 and MDSCs in RA is not yet fully understood. We investigated the relevance between the level of DKK-1 and the expression of MDSCs in different tissues and joint destruction in RA patients and collagen-induced arthritis (CIA) mouse models. Furthermore, the CIA mice were administered recombinant DKK-1 protein. The arthritis scores, bone destruction, and the percentage of MDSCs in the peripheral blood and spleen were monitored.In vitro, the differentiation of MDSCs into OCs was intervened with recombinant protein and inhibitor of DKK-1. The number of OCs differentiated and the protein expression of the Wnt/β-catenin signaling pathway were explored. The level of DKK-1 positively correlates with the frequency of MDSCs and bone erosion in RA patients and CIA mice. Strikingly, recombinant DKK-1 intervention significantly exacerbated arthritis scores and bone destruction, increasing the percentage of MDSCs in the peripheral blood and spleen in CIA mice.In vitroexperiments showed that recombinant DKK-1 promoted the differentiation of MDSCs into OCs, reducing the expression of β-catenin and TCF4 and increasing the expression of CyclinD1. In contrast, the DKK-1 inhibitor had the opposite effect. Our findings highlight that DKK-1 promoted MDSCs expansion in RA and enhanced the differentiation of MDSCs into OCs via targeting the Wnt/β-catenin pathway, aggravating the bone destruction in RA.