miR-450b-5p对成骨分化、骨生成和地塞米松抑制成骨的调控作用及机制研究

With the wide application of glucocorticoid and aging of population, the incidence rates of osteoporosis increased year after year which seriously damage the human health. The common pathology of different types of osteoporosis is the decreased differentiation capacity of mesenchymal stem cells into osteoblasts. miRNAs are considered most likely to be a key factor in the regulation of stem cell lineage specialization, since they have the multi-targeting property. Currently, the role and mechanism of miRNA in regulating osteogenesis, osteogenic differentiation is unclear and the correlation research of miRNAs with osteoporosis is rarely reported. Our previous study found that miR-450b-5p expression was positively correlated with the crucial osteogenic transcription factors ALP and OPN in osteoporosis. Overexpression of miR-450b-5p can promote MSCs to differentiate into osteoblasts in vitro. In this project, we will further study the correlation between miR-450b-5p and osteoporosis by a large number of samples of osteoporosis, and investigate the role and molecular mechanism of miR-450b-5p on osteogenesis and osteogenic differentiation of mesenchymal stem cells in vitro and in vivo. We also will clarify the effect of this miRNA in regulating the suppression of dexamethasone on osteogenic differentiation. Successful completion of these studies will provide new effective targets for prevention and treatment of osteoporosis and other related disorders.

人口老龄化及糖皮质激素的应用使骨质疏松症成为危害严重的常见性疾病。骨质疏松症发病本质是间充质干细胞向成骨分化能力的降低。miRNAs具有调控广泛和功能多效的特点，被认为是调控干细胞分化的关键因素。一些miRNAs被报道参与MSC向成骨分化的调控，但骨质疏松症相关的miRNA报道不多。为了找到既具有促进成骨分化又与骨质疏松症相关的miRNAs，我们通过miRNA表达谱芯片获得MSCs向成骨分化后显著上调的miRNAs。初步的相关性分析及功能预实验显示，miR-450b-5p与骨质疏松症骨样本中成骨性基因ALP和OPN的表达呈正相关，体外过表达miR-450b-5p后可促进MSC向成骨分化。本项目拟进一步探讨miR-450b-5p与骨质疏松症的相关性，miR-450b-5p对体外成骨分化、体内骨生成及地塞米松诱导成骨抑制的调控作用，阐明miR-450b-5p发挥作用的靶分子及调控通路。

人口老龄化及糖皮质激素的应用使骨质疏松症成为危害严重的常见性疾病。骨质疏松症发病本质是间充质干细胞向成骨分化能力的降低。miRNAs具有调控广泛和功能多效的特点，被认为是调控干细胞分化的关键因素。一些miRNAs被报道参与MSC向成骨分化的调控，但骨质疏松症相关的miRNA报道不多。为了找到既具有促进成骨分化又与骨质疏松症相关的miRNAs，我们通过miRNA表达谱芯片获得MSCs向成骨分化后显著上调的miRNAs。初步的相关性分析及功能预实验显示，miR-450b-5p与骨质疏松症骨样本中成骨性基因ALP和OPN的表达呈正相关，体外过表达miR-450b-5p后可促进MSC向成骨分化。本项目进一步探讨miR-450b-5p与骨质疏松症的相关性，并发现miR-450b-5p与小鼠骨发育呈正相关关系。一系列的体内外实验表明，miR-450b-5p在体外能够明显促进MSCs向成骨细胞分化，并且有效拮抗地塞米松引起的成骨抑制作用；在体内异位骨形成小鼠模型中，miR-450b-5p能够加速MSCs生成类骨质。生物信息学分析及靶基因预测提示miR-450b-5p可能通过直接靶向抑制BMP2信号通路抑制成员BMP3发挥促进成骨分化的作用。我们敲降BMP3后发现成骨分化明显受到抑制，且伴随着BMP2信号通路的激活，这与miR-450b-5p过表达对成骨分化的影响相一致。我们首次发现miR-450b-5p能够通过靶向下调BMP2通路抑制成员BMP3的表达，从而发挥其促进MSCs的成骨分化和骨生成作用，提示miR-450b-5p可能作为一个新的靶点用于临床上成骨分化及骨生成缺陷相关疾病的防治。