骨衰老进程中YB1蛋白调控骨髓间充质干细胞命运分化偏移的作用及机制

Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation. This switch results in increased adipocytes and decreased osteoblasts, contributing to age-related bone loss, but the underlying mechanism remains unclear. In the preliminary study, we found that the expression of Y-box binding protein-1(YB1) is gradually decreased during aging both in human and mice BMSCs. Knockdown the expression of YB1 in BMSCs promotes its adipogenic differentiation while inhibites its osteogenic differentiation. However, over-expression of YB1 in BMSCs had opposite effects. Based on these findings, we proposed a hypothesis that the decreased expression of YB-1 in BMSCs during aging affects its switch between osteogenic and adipogenic differentiation and the bone metabolism. To verify this hypothesis: 1) we will construct YB1 BMSCs-specific knockout mice, to investigate the role of YB1 in regulating the switch between osteogenic and adipogenic differentiation of BMSCs and the bone mass. 2) Through RNA Sequencing and ChIP-seq, to explore the underlying signal network of YB1 in regulating the switch between osteogenic and adipogenic differentiation of BMSCs. 3) By computer-aided drug design, to search for natural small molecule compounds which binds to YB1, then explore the effects of identified compounds on the switch between osteogenic and adipogenic differentiation of BMSCs and the bone metabolism. Together, this study will reveal novel insights and potential drug targets for the treatment of age-related osteoporosis.

机体衰老进程中，骨髓间充质干细胞（BMSCs）向成骨-成脂分化命运发生偏移，导致成骨细胞减少脂肪细胞增加，是引发老年性骨丢失的重要原因，但其具体机制不明。我们前期研究发现，Y盒结合蛋白1（YB1）在人和小鼠BMSCs衰老过程中呈下降趋势，体外干扰YB1抑制BMSCs成骨分化而促进其成脂分化；过表YB1则具有相反的效应。因此我们提出假说：“衰老时YB1蛋白表达下调影响BMSCs成骨-成脂分化命运偏移及骨代谢”。为验证此假说：1) 我们构建BMSCs特异性YB1基因条件敲除小鼠模型，在体内外观察BMSCs分化偏移及骨量变化；2) 通过RNA Sequencing和Chip-seq，构建YB1蛋白调控BMSCs分化偏移的信号网络；3) 通过计算机辅助药物设计，筛选出与YB1对接的天然小分子化合物并验证其对BMSCs分化偏移及骨代谢的作用，为老年性骨质疏松的治疗寻找新靶点与新思路。

骨髓间充质干细胞（BMSCs）衰老及分化偏移是导致老年相关的骨丢失的重要原因。选择性剪接（AS）作为一种重要的转录后调控方式，调控基因表达的多样性。然而，选择性剪接调控及相关的剪切因子在BMSCs衰老过程中的作用仍不明确。本研究中，我们发现小鼠和人类骨髓间充质干细胞中剪接因子Y盒结合蛋白1（YBX1）的表达随着年龄的增长而逐渐降低，并证明YBX1的缺失导致Fn1、Nrp2、Sirt2、Sp7和Spp1等基因的错误剪接，进一步促进BMSCs衰老和衰老过程中BMSCs分化偏移。在BMSCs中敲除Ybx1加速了小鼠的骨丢失，而过表达Ybx1则刺激骨形成。值得注意的是，我们发现了一种小的化合物-金松双黄酮，它能减弱YBX1的降解和改善老年小鼠的骨丢失。我们的研究表明，YBX1通过调控RNA剪接来精细地控制着BMSCs的命运，并为老年性骨质疏松症提供了潜在的治疗靶点。