Age-Related Kynurenine Accumulation Impairs miRNA and Hdac Epigenetic Regulation of the SDF-1 Axis Resulting in Bone Loss

与年龄相关的犬尿氨酸积累损害 SDF-1 轴的 miRNA 和 Hdac 表观遗传调节，导致骨质流失

• 批准号: 9973283
• 负责人: WILLIAM D HILL
• 金额: $ 52.39万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973283
• 关键词: Affect; Age; Age-Related Bone Loss; Aging; Amino Acids; Aryl Hydrocarbon Receptor; Bone Marrow; Bone Marrow Stem Cell; Bone Resorption; CXCL12 gene; CXCR4 Receptors; Cell Lineage; Cell Survival; Cell physiology; Cells; Data; Disease; Epigenetic Process; Extracellular Matrix; Family; Fatty acid glycerol esters; Functional disorder; Generations; Genes; Goals; Grant; HDAC3 gene; Homeostasis; Human; Immune system; Impairment; Inflammation; Intervention; Kynurenine; Laboratories; Lipids; Marrow; Mediating; Mediator of activation protein; Mesenchymal; Methods; MicroRNAs; Molecular; Mus; Musculoskeletal System; Obesity; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Oxides; Pathology; Pathway interactions; Pharmacological Treatment; Pharmacology; Population; Reactive Oxygen Species; Regulator Genes; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Stromal Cell-Derived Factor 1; Stromal Cells; Support Groups; System; Testing; Tryptophan; Tryptophan 2,3 Dioxygenase; Up-Regulation; Work; age related; base; bone; bone loss; bone mass; bone turnover; cytokine; enzyme activity; epigenetic regulation; genetic approach; genetic manipulation; impaired driving performance; in vitro testing; in vivo; mimetics; new therapeutic target; novel; novel therapeutics; osteogenic; osteoprogenitor cell; oxidation; prevent; progenitor; programs; skeletal tissue; stem; stem cells

The mechanisms involved in aging-related osteoporosis remain poorly defined, however, recent studies from our group, and others, suggest that it is a stem cell disease. We have been studying the role of the cytokine SDF-1 (CXCL12) and Hdac3 in bone marrow mesenchymal stem/stromal cell (BMSC) function and bone homeostasis. A critical problem is that aging triggers impaired localization, proliferation, survival, and differentiation of the osteogenic progenitor cell population in the bone marrow (BM), specifically BMSCs. A critical barrier to preventing these changes is identifying key regulatory pathways, and being able to alter or correct them. We have identified BMSC epigenetic changes in the microRNA miR-29b-1-5p, that appears to cross-talk with histone deacetylase 3 (Hdac3), a second epigenetic regulatory system. Further, we have identified that the oxidized tryptophan (TRP) metabolite kynurenine (KYN) alters these specific epigenetic regulatory molecules in BMSCs, which in turn directly, and via SDF-1 signaling pathways, affect cell survival, osteogenesis, osteoblastic lipid storage, and bone formation. Significantly, miR-29b-1-5p, which increases with aging in BMSCs, belongs to the miR29 family of miRNAs that have been shown to be critical in extracellular matrix homeostasis and osteogenesis. One novel aspect is that miR29b-1-5p is the “passenger strand”, which is normally thought to be degraded leaving the complementary miR-29b-1-3p “guide strand” as the functional miRNA; with aging, however, our data suggest that this passenger strand is an important effector of BMSC dysfunction. Importantly, miR-29b- 1-5p, which targets SDF-1, is upregulated by KYN while Hdac3 is down regulated leading to increased lipid storage and dysfunction in BM osteoprogenitor cells and OBs. Understanding the upstream mechanisms that drive these previously unknown age-associated changes in miR-29b-1-5p and Hdac3 is a critical goal because we have demonstrated that these two interacting systems regulate SDF-1 expression and suppress BMSC osteogenesis and survival pathways while increasing BM fat storage. We propose to test the hypothesis that the elevated, age-related levels of KYN drive the increased expression of miR-29b-1-5p and inhibition of Hdac3 expression, with downstream effects on bone homeostasis via SDF-1 and its receptor CXCR4, or directly by targeting additional osteogenic genes both in BMSCS and OBs. Our objectives are to test new hypotheses derived from our findings by manipulating the miRNAs and Hdacs we identified as changing with age in human/murine BMSCs to determine their effects on bone formation and turnover in vivo and at the molecular level on BMSC osteogenic function. We will test novel methods to reduce expression of these molecules, including inhibiting KYN generation, inhibiting KYN signaling pathways, or delivering synthetic anti-miRNAs to inhibit miR29b-1-5p. The impact of this project will be to clarify the roles of age-associated epigenetic changes in cross-talking BMSC miRNA and Hdac systems with the goal of identifying novel targets for reducing, or reversing, age-related bone loss and osteoporosis.

与衰老相关的骨质疏松症涉及的机制仍然很差，但是我们最近的研究 小组和其他人认为这是一种干细胞疾病。我们一直在研究细胞因子SDF-1的作用 （CXCL12）和HDAC3在骨髓间充质茎/基质细胞（BMSC）功能和骨稳态中。 一个关键的问题是，衰老触发了损害的定位，增殖，生存和分化 骨髓（BM）中的成骨祖细胞群，特别是BMSC。一个关键的障碍 防止这些变化是确定关键的监管途径，并能够更改或纠正它们。我们 已经确定了MicroRNA miR-29b-1-5p中的BMSC表观遗传变化，似乎与组蛋白交叉 脱乙酰基酶3（HDAC3），第二个表观遗传调节系统。此外，我们已经确定了氧化的 色氨酸（TRP）代谢物kynurenine（Kyn）改变了BMSC中的这些特定表观遗传调节分子 这又直接并通过SDF-1信号通路会影响细胞存活，成骨，成骨细胞脂质 存储和骨形成。值得注意的是，随着BMSC的衰老而增加的miR-29b-1-5p属于 MiR29 miRNA家族在细胞外基质体内稳态和 成骨。一个新颖的方面是mir29b-1-5p是“乘客链”，通常被认为是 退化，将完整的miR-29b-1-3p“导链”作为功能miRNA；但是，随着衰老 我们的数据表明，该乘客链是BMSC功能障碍的重要效应因子。重要的是，mir-29b- 靶向SDF-1的1-5P由Kyn更新，而HDAC3被调节导致脂质增加 在BM破骨剂细胞和OBS中的存储和功能障碍。了解上游机制 驱动这些以前未知的年龄相关的变化，MiR-29b-1-5p和HDAC3是一个关键目标，因为 我们已经证明，这两个相互作用的系统调节SDF-1表达并抑制BMSC 成骨和生存途径，同时增加BM脂肪储存。我们建议检验以下假设 Kyn的升高，与年龄相关的水平驱动miR-29b-1-5p的表达增加和HDAC3的抑制 表达，通过SDF-1及其接收器CXCR4对骨体内平衡产生下游影响，或直接通过 靶向BMSC和OBS中的其他成骨基因。我们的目标是检验新假设 通过操纵miRNA和HDACS，我们确定为随着年龄的增长而变化，从我们的发现中得出 人/鼠BMSC确定它们对体内骨形成和周转的影响以及分子的影响 BMSC成骨功能的水平。我们将测试新方法以减少这些分子的表达， 包括抑制Kyn产生，抑制Kyn信号通路或将合成抗MIRNA传递到 抑制miR29b-1-5p。该项目的影响是阐明与年龄相关的表观遗传变化的作用 在交叉讲话中，BMSC miRNA和HDAC系统的目的是识别减少或 逆转，与年龄相关的骨质流失和骨质疏松症。