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间充质细胞又称为间充质干细胞（Mesenchymal stem cells,MSC）、间质干细胞、间叶干细胞，泛指一类具有一定分化潜能、可以分化成多种细胞类型、具有组织修复功能的多能基质细胞群。骨髓间充质细胞分化为成骨细胞是骨形成的关键步骤。然而成骨分化早期阶段所涉及的机制尚不清楚。前期研究发现FHL2是LIM蛋白超家族中LIM-only亚类的成员，在小鼠和人类MSCs中地塞米松诱导的早期成骨细胞分化过程中该亚类显著上调。此外，FHL2可促进成骨细胞转录因子Runx2、碱性磷酸酶（Alkaline phosphatase,ALP）、I型胶原蛋白A1 (Collagen type I alpha 1 chain,COL1A1)的表达以及间充质细胞的细胞外基质矿化（Extracellular matrix mineralization）。本研究使用sh-RNA敲除FHL2观察MSCs中重组腺相关病毒（Recombination adeno-associated virus, rAAV）诱导的成骨细胞标志基因表达情况。结果发现FHL2与β-catenin相互作用，后者是Wnt信号诱导的骨形成中的关键参与者。FHL2-β-catenin相互作用增强了β-catenin核转位和TCF/LEF转录，导致Runx2和ALP表达增加，而Wnt抑制剂DKK1可抑制这种表达。这些结果表明，FHL2是间充质细胞分化成成骨细胞的内源性激活剂，它通过激活Wnt/β-catenin信号依赖性Runx2的表达，介导重组腺相关病毒诱导的间充质干细胞成骨分化。
Abstract：Mesenchymal cells, also known as mesenchymal stem cells(MSC), refer to a population of multipotent stromal cells with differentiation potential into various cell types and tissue repair functions.Differentiation of bone marrow-derived mesenchymal cells into osteoblasts is a critical step in bone formation.However, the mechanisms involved in the early stages of osteogenic differentiation remain unclear. Previous studies have identified FHL2 as a member of the LIM-only subclass of the LIM protein superfamily, which is significantly upregulated during dexamethasone-induced early osteoblast differentiation in both mouse and human MSCs. Additionally, FHL2 promotes the expression of osteoblast transcription factor Runx2, alkaline phosphatase(ALP), collagen type I alpha 1 chain(COL1A1), and extracellular matrix mineralization of mesenchymal cells. In this study, sh-RNA-mediated knockdown of FHL2 was employed to examine the expression of osteoblast marker genes induced by recombinant adeno-associated virus(rAAV) in MSCs. The results revealed that FHL2 interacts with β-catenin, a key player in bone formation via Wnt signaling. The FHL2-β-catenin interaction enhances β-catenin nuclear translocation and TCF/LEF-mediated transcription, resulting in increased Runx2 and ALP expression, which is inhibited by the Wnt antagonist DKK1. These findings suggest that FHL2 serves as an endogenous activator of mesenchymal cell differentiation into osteoblasts, mediating rAAV-induced osteogenic differentiation through activation of Wnt/β-catenin signalingdependent Runx2 expression.
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基本信息:
DOI：10.13242/j.cnki.bingduxuebao.240269
中图分类号:R580
引用信息:
[1]蒋晓伟,王强,缪逸鸣等.重组腺相关病毒调控间充质干细胞成骨分化的作用机制[J].病毒学报,2025,41(02):479-487.DOI:10.13242/j.cnki.bingduxuebao.240269.
基金信息: