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

项目3：营养素介导的SDF-1相关变化导致骨丢失。 衰老触发主要骨髓干细胞群体（包括骨髓间充质基质/干细胞（BMSC））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节BMSC的存活和分化。我们认为，这些途径中至少有两种通过调节趋化因子基质细胞衍生因子1（SDF-1，或CXCL 12）及其主要受体CXCR 4在很大程度上作用于骨稳态。 有证据表明，营养调节激素瘦素通过胰岛素样生长因子1（IGF-1）和二肽基肽酶IV（DPP 4）调节SDF-1和CXCR 4。我们报告了SDF-1的全身和骨髓细胞表达随年龄的变化。我们最近第一次证明，增加瘦素水平，在老年小鼠中下降，使老年小鼠中的循环SDF-1水平恢复到年轻小鼠中所见的水平。SDF-1靶向microRNA（miRNAs）的表达也在老年小鼠的BMSC中发生了变化。 这些发现表明，在老化的BMSCs中功能丧失与SDF-1表达失调有关。我们认为营养对BMSCs和骨稳态的影响部分是通过SDF-1/CXCR 4途径控制的。我们进一步表明，SDF-1在BMSC移植模型中增加BMSC植入和骨生长。在本申请中，我们提出测试以下假设：1）BMSC CXCR 4和骨髓SDF-1水平对BMSC和成骨细胞存活、分化和成骨功能至关重要，以及2）通过瘦素/IGF-1和膳食蛋白的营养信号传导调节BMSC表达和对SDF-1/CXCR 4的应答。我们将使用新的转基因小鼠（DPP 4-/-），分子工具（siRNA，miRNA载体）和药理学试剂，并将与其他计划项目Pis合作，以测试这些假设。

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.