NUTRIENT MEDIATED AGE-RELATED CHANGES IN SDF-1 RESULTS IN BONE LOSS

项目3：营养物质介导的SDF-1的年龄相关变化导致骨丢失。 衰老导致包括骨髓间充质/干细胞(BMSCs)在内的主要骨髓干细胞群体的定位、增殖、存活和分化受损。许多参与营养摄入和营养反应的经典途径调控着骨髓间充质干细胞的存活和分化。我们认为，这些途径中至少有两个在很大程度上通过调节趋化因子基质细胞衍生因子1(SDF-1，或CXCL12)及其主要受体CXCR4来作用于骨稳态。 有证据表明，营养调节激素瘦素通过胰岛素样生长因子1(LGF-1)和二肽基肽酶IV(DPP4)调节SDF-1和CXCR4。我们报告了SDF-1在全身和骨髓细胞中的表达随年龄的变化。我们最近首次证明，在老年小鼠中，瘦素水平的升高会下降，而老年小鼠循环中的SDF-1水平又会恢复到年轻小鼠的水平。SDF-1靶向的microRNAs(MiRNAs)在老年小鼠的BMSCs中的表达也发生了变化。 这些发现提示衰老的BMSCs功能丧失可能与SDF-1表达失调有关。我们认为，营养对骨髓间充质干细胞的影响和骨稳态部分是通过SDF-1/CXCR4途径控制的。我们进一步证明，在骨髓间充质干细胞移植模型中，SDF-1促进了骨髓间充质干细胞的植入和骨生长。在这一应用中，我们提出了以下假设：1)BMSC CXCR4和骨髓中SDF-1的水平对BMSC和成骨细胞的存活、分化和成骨功能至关重要；2)通过瘦素/IGF-1和饮食蛋白调节BMSC的表达和对SDF-1/CXCR4的反应。我们将使用新的转基因小鼠(DPP4-/-)、分子工具(siRNA、miRNA载体)和药理学试剂，并将与其他项目PIS协调工作来验证这些假设。

Project 3: Nutrient Mediated Age-Related Changes In SDF-1 Results In Bone Loss. Aging triggers impaired localization, proliferation, survival, and differentiation of the main bone marrow stem cell populations, including bone marrow mesenchymal stromal/stem cells (BMSCs). A number of classical pathways involved in nutrient intake and nutrient response regulate BMSC survival and differentiation. We propose that at least two of these pathways are acting on bone homeostasis in significant part through regulation of the chemokine stromal cell-derived factor 1 (SDF-1, or CXCL12) and its major receptor CXCR4. There is evidence that the nutrient-regulated hormone, leptin, modulates SDF-1 and CXCR4 through insulinlike growth factor 1 (lGF-1) and dipeptidyl pepfidase IV (DPP4). We report that systemic and bone marrow cell expression of SDF-1 changes with age. We have recenfiy shown, for the first time, that increasing leptin levels, which decline in aged mice, returns circulafing SDF-1 levels in aged mice to levels seen in young mice. The expression of SDF-1-targeting microRNAs (miRNAs) is also altered in BMSCs from aged mice. These findings suggest the possibility that loss of funcfion in aging BMSCs is linked to the dysregulated SDF-1 expression. We propose that nutrient effects on BMSCs and bone homeostasis are controlled in part through the SDF-1/CXCR4 pathway. We have further shown that SDF-1 increases BMSC engraftment and bone growth in a BMSC transplantation model. In this applicafion we propose to test the hypotheses that: 1) BMSC CXCR4 and bone marrow levels of SDF-1 are critical to BMSC and osteoblast survival, differentiation and osteogenic funcfion, and 2) Nutrient signaling through leptin/IGF-1 and dietary protein modulate BMSC expression and response to SDF-1/CXCR4. We will use novel transgenic mice (DPP4-/-), molecular tools (siRNA, miRNA vectors), and pharmacologic agents, and will work in coordination with the other program project Pis to test these hypotheses.