LncRNA-DYSOD作为ceRNA调控Runx2介导BMSCs成骨/成脂分化平衡的机制研究

With the gradual intensification of aging problem in China, osteoporosis has become a common and frequently-occurring disease among middle-aged and elderly people, which as a consequence seriously endangers the health of our population. Therefore, there is a great scientific significance and clinical value to explore the pathogenesis of osteoporosis. In our preliminary study, we discovered a long noncoding RNA (lncRNA-DYSOD) had obviously been downregulated in the bone tissue of osteoporotic mice models. Moreover, the knockdown of lncRNA-DYSOD could significantly inhibit the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and promote the adipogenic differentiation of BMSCs, indicating that lncRNA-DYSOD might involved in regulating the balance of osteogenic/adipogenic differentiation of BMSCs. However, the underlying molecular mechanism still remains to be illuminated. Therefore, our project intends to apply various in vivo and in vitro techniques to study the following contents: (1) to clarify the regulatory effect of lncRNA-DYSOD in osteoporosis; (2) to elucidate the molecular mechanism of lncRNA-DYSOD in regulating osteogenic/adipogenic differentiation of BMSCs during osteoporosis process; (3) to explore whether lncRNA-DYSOD can become a new target for the clinical prevention and treatment of osteoporosis. This project will provide us new ideas for the prevention and treatment of osteoporosis.

随着我国人口老龄化的日趋加剧，骨质疏松已成为中老年人的常见病和多发病，严重危害我国人口健康。因此，深入探究骨质疏松的致病机理对其防治具有重要的科学意义和临床应用价值。在前期研究中，我们在骨质疏松模型小鼠骨组织中筛选出一个表达下调的lncRNA（lncRNA-DYSOD），并发现敲减该lncRNA可抑制骨髓间充质干细胞（BMSCs）向成骨分化、促进其向成脂分化，提示lncRNA-DYSOD可能通过影响BMSCs成骨/成脂分化平衡调控骨质疏松的发生，但其分子机制仍需进一步阐明。因此，本项目拟运用多种在体、离体实验技术研究以下内容：（1）揭示lncRNA-DYSOD在骨质疏松中的调控作用；（2）阐明lncRNA-DYSOD参与调控BMSCs成骨/成脂分化平衡，进而影响骨质疏松进程的分子机制；（3）探讨lncRNA-DYSOD能否成为防治骨质疏松的新靶点。本项目将为临床骨质疏松的防治提供新思路。

骨质疏松症是一种以骨量降低、骨组织微结构被破坏为特征，进而引起骨的脆性增加和易于骨折的代谢性疾病。随着我国逐步进入老龄化社会，骨质疏松症的发病率不断升高，给家庭和社会带来了沉重的负担。因此，揭示骨质疏松症的病因和形成机制，寻找诱发骨质疏松症的关键靶点并进行适当干预，对于骨质疏松症的防治具有重要的科学意义和临床应用价值。骨髓间充质干细胞（BMSCs）是骨内普遍存在的一种成体干细胞，具有自我更新能力和多向分化潜能。BMSCs是骨内成骨细胞和脂肪细胞的重要来源，BMSCs向成骨分化能力降低与骨质疏松症的发生密切相关，且骨质疏松患者骨密度的降低亦与骨内脂肪组织增多有关。因此，探究BMSCs成骨/成脂分化的调控机制，已成为当今骨质疏松症防治领域的研究热点和难点。长链非编码RNA（LncRNA）是一类转录本长度超过200 nt的RNA分子，它们并不编码蛋白，而是以RNA的形式在多种层面上调控基因的表达。近年来研究表明，lncRNA广泛参与了基因组印记，X染色体沉默以及染色质修饰，转录激活，转录干扰，核内运输等多种重要的调控过程。在本项目研究中，我们在骨质疏松症小鼠模型骨组织中筛选出一个表达下调的lncRNA（lncRNA-OPAR），并证实过表达lncRNA-OPAR促进骨髓间充质干细胞向成骨分化，抑制其向成脂分化。相反，敲除lncRNA-OPAR抑制骨髓间充质干细胞向成骨分化，促进其向成脂分化。进一步的研究证实，lncRNA-OPAR可通过靶向miR-297b/Csnk2a2通路参与调控骨髓间充质干细胞成骨/成脂分化转换。以上研究揭示，以非编码RNA为靶点可调控BMSCs向成骨/成脂定向分化。因此，针对以上靶点的转基因药物治疗可有效提高BMSCs的移植和分化效率，从而为实现骨质疏松症的防治提供理论基础和实验依据。