MicroRNA-195-5p Regulates Osteogenic Differentiation of Periodontal Ligament Cells Under Mechanical Loading
MicroRNA-195-5p Regulates Osteogenic Differentiation of Periodontal Ligament Cells Under Mechanical Loading
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MicroRNA-195-5p 调节机械负荷下牙周膜细胞的成骨分化
DOI：
10.1002/jcp.25856
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发表时间：
2017-12-01
影响因子：
5.6
通讯作者：
Fan, Mingwen
中科院分区：
文献类型：
--
作者：
Chang, Maolin;Lin, Heng;Fan, Mingwen
成骨分化和骨形成受到包括microRNA（miRNAs）在内的多种因素的严格调控。然而，在机械负荷诱导的人牙周膜细胞（PDLCs）成骨分化过程中，miRNA的表达模式和功能仍不清楚。在这里，我们研究了差异表达的miRNA-195- 5 p在小鼠的牙周组织正畸机械负荷下，并在原代人PDLCs暴露于模拟的张力应变。miR-195- 5 p在成骨细胞中表达下调，与成骨分化呈负相关。miR-195- 5 p的过表达显著抑制PDLC在循环张力应变（CTS）下的分化，而miR-195- 5 p的功能抑制产生相反的效果。进一步的实验证实，WNT家族成员3A（WNT 3A）、成纤维细胞生长因子2（FGF 2）和骨形态发生蛋白受体-1A（BMPR 1A）是miR-195- 5 p的直接靶点，这些蛋白质对成骨活性和稳定性很重要。机械负荷增加了WNT 3A、FGF 2和BMPR 1A蛋白水平，而miR-195- 5 p抑制了WNT 3A、FGF 2和BMPR 1A蛋白表达。WNT、FGF和BMP信号通路参与CTS诱导PDLCs成骨分化。进一步的研究证实，重新引入WNT 3A和BMPR 1A可以挽救miR-195- 5 p对PDLCs成骨分化的抑制。我们的研究结果首次证明miR-195- 5 p是一种机械敏感基因，在机械负荷诱导的成骨分化和骨形成中起重要作用。
Osteogenic differentiation and bone formation are tightly regulated by several factors, including microRNAs (miRNAs). However, miRNA expression patterns and function during mechanical loading-induced osteogenic differentiation of human periodontal ligament cells (PDLCs) remain unclear. Here, we investigated the differential expression of miRNA-195-5p in the periodontal tissues of mice under orthodontic mechanical loading and in primary human PDLCs exposed to a simulated tension strain. The miR-195-5p was observed to be down-regulated and negatively correlated with osteogenic differentiation. Overexpression of miR-195-5p significantly inhibited PDLC differentiation under cyclic tension strain (CTS), whereas the functional inhibition of miR-195-5p yielded an opposite effect. Further experiments confirmed that WNT family member 3A (WNT3A), fibroblast growth factor 2 (FGF2), and bone morphogenetic protein receptor-1A (BMPR1A), proteins important for osteogenic activity and stability, were direct targets of miR-195-5p. Mechanical loading increased the WNT3A, FGF2, and BMPR1A protein levels, while miR-195-5p inhibited WNT3A, FGF2, and BMPR1A protein expression. WNT, FGF, and BMP signaling were involved in osteogenic differentiation of PDLCs under CTS. Further study confirmed that reintroduction of WNT3A and BMPR1A can rescue the inhibition of miR-195-5p on osteogenic differentiation of PDLCs. Our findings are the first to demonstrate that miR-195-5p is a mechanosensitive gene that plays an important role in mechanical loading-induced osteogenic differentiation and bone formation.