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: 8967197
• 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/8967197
• 关键词: Acute; Adipocytes; Affect; Age; Age-Related Bone Loss; Age-Related Osteoporosis; 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; Health Care Costs; Hip Fractures; Homeostasis; Homing; Human; In Vitro; Inflammatory; 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; Reporting; Research; Risk; Role; Serum; Serum Markers; Signal Transduction; Site; Spinal Fractures; Stem cells; Stroke; Stromal Cell-Derived Factor 1; Testing; Time; Tissues; Transplantation; Traumatic injury; United States National Institutes of Health; Veterans; Woman; Work; age effect; age related; bone; bone age; 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; research study; response; stem cell differentiation; stem cell population; substantia spongiosa

DESCRIPTION (provided by applicant): 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 wth 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 determine experimentally if such miRNAs affect 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 traumatic 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.

描述（由申请人提供）： 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，对于女性来说，这是最令人衰弱的疾病之一，这些疾病占我们的资深人口份额越来越大。髋关节和椎骨骨折，骨质疏松症患有主要风险，导致独立性丧失，疼痛，甚至潜在的严重心脏和脑部病毒，以及死亡率的增加。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，并导致与年龄相关的骨质流失。在外周血中，血液SDF-1通过循环二乙酰丙肽酶C​​D26（二捷乙酰肽酶4，dpp4）迅速转化为N末端内肽酶切割形式。 SDF-1的裂解形式与SDF-1受体CXCR4结合并阻断，但不会激活它。它实际上成为抑制剂。由于DPP4对SDF-1的快速变化，但其总崩溃和去除速度较慢，我们的研究表明，血液和骨髓中的大多数SDF-1都是无效/抑制性形式。我们假设的一部分是，如果非活性形式的水平缓慢上升并保持衰老，那么CXCR4信号长期降低，这将对骨骼产生负面影响，从而减少BMSC的数量并减少骨形成。有越来越多的证据表明，BM间充质干细胞（BMSC）需要CXCR4信号传导以维持祖细胞群体并启动和支持骨化。重要的是，我们实验室的临床前鼠研究表明，包括DPP4旋转形式在内的总SDF-1的循环水平随着小鼠的年龄而增加，并且在实验中增加了DPP4-旋转的SDF-1年轻小鼠的血浆水平，从而减少了骨形成血清标记，并显着降低了骨骼的骨骼体积和骨骼骨骼的体积。这导致了一项资助的NIH PO1赠款，以确定SDF-1同工型在随着年龄的增长的调节中的作用。此处提出的研究是要查看我们的假设和观察结果在人类中是否正确：我们建议测试新的假设，即人类在人类中增加了DPP4-裂解的SDF-1同工型是年龄和疾病相关的骨质损失的重要因素。我们建议评估循环水平，骨髓，SDF-1（DPP4旋转和非切割）水平，DPP4活性，以及​​这些同工型对人类BMSC在体外和骨骼形成和骨骼形成和质量/密度的影响。我们将在不同年龄的患者的血清和骨髓中测量SDF-1同工型以及DPP4，并将其与它们的骨密度和体积以及骨形成或分解的血清标记物相关。我们还将确定相对于年龄匹配的对照组，这些SDF-1和DPP4参数是否有变化。我们进一步建议确定用于糖尿病治疗中FDA批准药物的骨骼形成的影响，该药物通过调节DPP4活性（例如西捷蛋白）来起作用。我们将确定与对照组相比，接受这些DPP4抑制剂治疗的糖尿病患者是否显示出骨形成的改善。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，以确定针对SDF-1轴和成骨基因的miRNA中是否存在相关的变化。我们将通过实验确定此类miRNA是否影响BMSC细胞命运。这项工作可能会迅速导致已经获得FDA认可的DPP4抑制剂的临床试验，作为一种新型的骨质疏松症的新型亲骨重塑治疗，作为当前有问题的抗复制疗法的替代或增强。在后续研究中，急性抑制DPP4也可能具有增加骨修复速率的价值，通过增加SDF-1的活跃形式，以增加断裂后干细胞的归巢和成骨诱导，或其他对骨骼的创伤性损伤，对VA和DOD的关键需求。长期的这项工作打开了使用特定miRNA调节的潜力，以随着年龄的增长并预防骨质疏松症来调节BMSC的成骨环境。