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报告不足，可能存在于高达31%的男性VA患者中。此外，它是对妇女最具破坏性的疾病之一--她们在我们的退伍军人人口中所占的比例越来越大。髋部和椎骨骨折是骨质疏松症的主要风险，导致丧失独立性、疼痛，甚至潜在的严重心脏和脑部疾病，以及死亡率增加。我们的主要假设是，细胞因子基质衍生因子1（SDF-1，又名CXCL 12）在外周循环中随着年龄的增长而增加，并导致年龄相关的骨丢失。在外周血中，SDF-1通过循环二肽基肽酶CD 26（二肽基肽酶4，DPP 4）快速转化为N-末端内肽酶裂解形式。SDF-1的裂解形式结合并阻断SDF-1受体CXCR 4，但不激活它，它实际上成为一种抑制剂。由于DPP 4对SDF-1的快速改变，但其完全分解和清除较慢，我们的研究表明血液和骨髓中的大部分SDF-1是无活性/抑制形式。我们的部分假设是，如果非活性形式的水平缓慢上升，并随着年龄的增长而保持不变，那么CXCR 4信号转导长期减少，这将对骨骼产生负面影响，减少BMSC的数量并减少骨形成。越来越多的证据表明，骨髓间充质干细胞（BMSC）需要CXCR 4信号传导来维持祖细胞群并启动和支持骨生成。重要的是，我们实验室的临床前小鼠研究表明，总SDF-1的循环水平，包括DPP 4裂解形式，随着小鼠年龄的增长而增加，并且实验性地增加年轻小鼠中DPP 4裂解的SDF-1的血浆水平会降低骨形成血清标志物并显著降低骨小梁体积和骨密度。这导致了NIH PO 1基金的资助，以确定SDF-1亚型在调节小鼠骨形成中的作用。这里提出的研究是为了看看我们在小鼠中的假设和观察是否在人类中是正确的：我们建议测试新的假设，即在人类中增加的DPP 4切割的SDF-1亚型是年龄和疾病相关骨质流失的重要因素。我们建议评估循环水平，骨髓，SDF-1（DPP 4裂解和非裂解）水平，DPP 4活性，以及这些亚型对人BMSC的体外成骨活性和体内骨形成和质量/密度的影响。我们将测量不同年龄患者血清和骨髓中的SDF-1亚型沿着DPP 4，并将其与骨密度和体积以及骨形成或分解的血清标志物相关联。我们还将确定骨质疏松症患者相对于年龄匹配的对照组，这些SDF-1和DPP 4参数是否发生变化。我们进一步提出确定FDA批准的用于糖尿病治疗的药物对骨形成的影响，这些药物通过调节DPP 4活性（例如西他格列汀）起作用。我们将确定接受这些DPP 4抑制剂治疗的糖尿病患者与对照组相比是否显示出骨形成的改善。最后，我们将使用分离的人类患者BMSC来确定DPP 4切割的SDF-1是否降低BMSC细胞存活、增殖和成骨潜力。此外，将评估这些人BMSC以确定靶向SDF-1轴和成骨基因的miRNA是否存在年龄相关变化。我们将通过实验确定这些miRNAs是否影响BMSC细胞的命运。这项工作可能会迅速导致已经FDA批准的DPP 4抑制剂作为骨质疏松症的新型促骨重塑治疗的临床试验，作为目前有问题的抗重塑治疗的替代或增强。在后续研究中，DPP 4的急性抑制也可能通过增加SDF-1的活性形式来增加骨折或其他骨创伤后的干细胞归巢和成骨诱导，从而增加骨修复率，这是VA和DoD的关键需求。长期而言，这项工作开辟了利用特定miRNA调节BMSC随年龄增长的成骨环境并预防骨质疏松症的可能性。