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: 10375583
• 负责人: WILLIAM D HILL
• 金额: $ 49.27万
• 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/10375583
• 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.

然而，我们最近的研究表明，与衰老相关的骨质疏松症的机制仍然不明确