Bad to the Bone: Age-related Increases in Serum SDF-1 Leads to Bone Loss with Age

对骨骼有害：血清 SDF-1 随年龄增长而增加，导致骨质流失

• 批准号: 8810590
• 负责人: WILLIAM D HILL
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810590
• 关键词: Acute; Adipocytes; Affect; Age; Age-Related Bone Loss; Aging; American; Antidiabetic Drugs; Binding; Blood; Blood Circulation; Bone Density; Bone Growth; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Regeneration; Bone remodeling; Brain; CSF3 gene; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cardiac; Cell Survival; Cells; Cleaved cell; Clinical Trials; Comorbidity; Development; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Disease; Endopeptidases; Engraftment; Environment; Epigenetic Process; Excision; FDA approved; Family; Follow-Up Studies; Fracture; Funding; Gene Expression; Genes; Grant; Health Care Costs; Hip Fractures; Homeostasis; Homing; Human; In Vitro; Inflammatory; Injury; Insulin-Like Growth Factor I; Laboratories; Lead; Leptin; Link; Maintenance; Measures; Mesenchymal; Mesenchymal Stem Cells; MicroRNAs; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; N-terminal; Orthopedics; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Pain; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Play; Population; Post-Translational Protein Processing; Prevalence; Process; Production; Protein Isoforms; Public Health; Receptor Signaling; Reducing Agents; Regulation; Relative (related person); Reporting; Research; Risk; Role; Serum; Serum Markers; Signal Transduction; Site; Spinal Fractures; Stem cells; Stroke; Stromal Cell-Derived Factor 1; Testing; Time; Tissues; Transplantation; United States National Institutes of Health; Veterans; Woman; Work; age effect; age related; bone; bone loss; bone quality; cell motility; chemokine; cytokine; density; diabetic; diabetic patient; disability; improved; in vitro activity; in vivo; inhibitor/antagonist; lipid biosynthesis; male; men; mortality; novel; osteoblast differentiation; osteogenic; peripheral blood; pre-clinical; prevent; protein expression; public health relevance; research study; response; stem cell differentiation; stem cell population; substantia spongiosa

Osteoporosis is under-reported in men and may be present in up to 31% of male VA patients. Further, it is among the most debilitating disorders for women - who make up an increasingly larger share of our veteran population. Hip and vertebral fractures, major risks with osteoporosis, lead to loss of independence, pain, even potentially serious cardiac and brain morbidities, as well as increased mortality. Our main hypothesis is that the cytokine stromal-derived factor 1 (SDF-1, aka CXCL12) is increased in the peripheral circulation with age and contributes to age-associated bone loss. In the peripheral blood SDF-1 is rapidly converted to an N-terminal endopeptidase-cleaved form by the circulating dipetidlylpeptidase CD26 (dipetidlylpeptidase 4, DPP4). The cleaved form of SDF-1 binds to and blocks the SDF-1 receptor CXCR4, but does not activate it. It becomes in effect an inhibitor. Because of the quick alteration of SDF-1 by DPP4, but its slower total breakdown and removal, our research suggests the majority of the SDF-1 in the blood and bone marrow is of the inactive/inhibitory form. Part of our hypothesis is that if the level of the inactive form rises slowly, and stays up with aging, then CXCR4 signaling is reduced long-term and this will have a negative impact on bone, reducing the number of BMSCs and reducing bone formation. There is increasing evidence that CXCR4 signaling is needed for BM mesenchymal stem cells (BMSCs) to maintain a progenitor cell population and to initiate and support osteogenesis. Importantly, preclinical murine studies from our laboratory have shown that circulating levels of total SDF-1, including the DPP4-cleaved form, increase with age in mice and that experimentally increasing the plasma level of DPP4-cleaved SDF-1 in young mice reduces bone formation serum markers and significantly decreases trabecular bone volume and bone density. This led to a funded NIH PO1 grant to determine the role of SDF-1 isoforms in the regulation of murine bone formation with age. The research studies proposed here are to see if our hypotheses and observations in mice are true in humans: We propose to test the novel hypothesis that in humans increased DPP4-cleaved SDF-1 isoforms are important factors in age-and disease-associated bone loss. We propose to assess the levels of circulating, and bone marrow, SDF-1 (DPP4-cleaved and non-cleaved) levels, DPP4 activity, and the effects of these isoforms on human BMSC's osteogenic activity in vitro and bone formation and quality/density in vivo. We will measure SDF-1 isoforms along with DPP4 in the serum and bone marrow of patients of different ages, and correlate this with their bone density and volume, as well as serum markers of bone formation or breakdown. We will also determine if there are changes in these SDF-1 and DPP4 parameters in patients with osteoporosis relative to age-matched controls. We further propose to determine the effects on bone formation of FDA-approved drugs in use for diabetic therapy, which act by regulating DPP4 activity (e.g. sitaglitin). We will determine if diabetic patients receiving treatment with these DPP4 inhibitors show improved bone formation compared to controls. Finally, we will use isolated human patient BMSCs to determine if DPP4 cleaved SDF-1 reduces BMSC cell survival, proliferation, and osteogenic potential. Additionally, these human BMSCs will be assessed to determine if there are age-associated changes in miRNAs targeting the SDF-1 axis and osteogenic genes. We will deteremine experimentally if such miRNAs effect BMSC cell fate. This work could rapidly lead to clinical trials of already FDA approved DPP4 inhibitors as a novel pro-bone remodeling treatment for osteoporosis as a replacement, or enhancement, of current problematic anti-remodeling therapies. In follow up studies, acute inhibition of DPP4 may also have value in increasing bone repair rates via increasing the active form of SDF-1 to increase stem cell homing and osteogenic induction following fracture, or other truamatic injury to bone, a critical need for the VA and DoD. Longer-term this work opens the potential to use regulation of specific miRNAs to regulate the osteogenic environment for BMSCs with age and to prevent osteoporosis.

骨质疏松症在男性中的报告不足，可能出现多达31％的男性VA患者。此外，是 在女性最令人衰弱的疾病中，她们占我们退伍军人的份额越来越大 人口。臀部和椎骨骨折，骨质疏松症的主要风险，导致独立性，疼痛，甚至是 潜在的严重心脏病和脑部发病率以及死亡率增加。我们的主要假设是 周围循环中的细胞因子基质衍生因子1（SDF-1，又名CXCL12）随着年龄的增长而增加 有助于与年龄相关的骨质流失。在外周血中，SDF-1迅速转化为N末端 内肽酶切割的形式是通过循环二乙酰磷酸酶CD26（二乙酰肽酶4，DPP4）的形式。这 SDF-1的裂解形式与SDF-1受体CXCR4结合并阻断，但不会激活它。它进入了 作用抑制剂。由于DPP4对SDF-1的快速更改，但总体故障较慢和 删除，我们的研究表明，血液和骨髓中的大多数SDF-1是 非活性/抑制形式。我们假设的一部分是，如果非活动形式的水平缓慢上升并保持 随着衰老，CXCR4信号长期降低，这将对骨骼产生负面影响，从而减少 BMSC的数量和减少骨形成。有越来越多的证据表明CXCR4信号是 BM间充质干细胞（BMSC）需要维持祖细胞群并启动和启动和 支持成骨。重要的是，我们实验室的临床前鼠研究表明，循环 总SDF-1的水平，包括DPP4旋转的形式，随着小鼠的年龄而增加，并且在实验上 增加年轻小鼠中DPP4旋转的SDF-1的血浆水平降低了骨形成血清标记 并显着降低小梁骨体积和骨密度。这导致了资助的NIH PO1赠款 确定SDF-1同工型在随着年龄的增长的调节中的作用。研究 这里提出的是查看我们在人类中的假设和观察结果是正确的：我们建议测试 新的假设是，在人类中增加了DPP4旋转的SDF-1同工型是年龄和年龄的重要因素 与疾病相关的骨质流失。我们建议评估循环水平和骨髓的水平，SDF-1 （DPP4旋转和未切割的）水平，DPP4活性以及这些同工型对人BMSC的影响 体外和骨形成的成骨活性以及体内质量/密度。我们将测量SDF-1同工型 与不同年龄的患者的血清和骨髓中的DPP4一起，并将其与骨头相关 密度和体积，以及骨形成或分解的血清标记。我们还将确定是否在那里 这些SDF-1和DPP4参数的变化相对于年龄匹配的骨质疏松症患者 控件。我们进一步建议确定对FDA批准药物的骨形成的影响 糖尿病疗法，通过调节DPP4活性（例如西捷蛋白）起作用。我们将确定糖尿病患者是否 与对照组相比，使用这些DPP4抑制剂接受治疗显示骨形成改善。最后， 我们将使用孤立的人类患者BMSC来确定DPP4是否裂解SDF-1会降低BMSC细胞的存活， 增殖和成骨潜力。此外，将评估这些人类BMSC，以确定是否存在 是针对SDF-1轴和成骨基因的miRNA中与年龄相关的变化。我们将恶化 在实验上，如果这种miRNA影响BMSC细胞命运。这项工作可能会迅速导致已经进行的临床试验 FDA批准的DPP4抑制剂是一种新型的骨重塑治疗骨质疏松症作为替代品， 或增强目前有问题的抗塑料疗法。在后续研究中，急性抑制 DPP4也可能通过增加SDF-1的主动形式增加骨修复率以增加而具有价值 断裂后干细胞的归巢和成骨诱导，或其他对骨骼的损伤，急需 对于VA和DOD。长期的这项工作打开了使用特定miRNA调节调节的潜力 BMSC随着年龄的增长和预防骨质疏松症的成骨环境。