Impact of Endotoxin on Fibroblast Growth Factor 23 Production by Osteocytes

内毒素对骨细胞产生成纤维细胞生长因子 23 的影响

• 批准号: 8749091
• 负责人: Jason Stubbs
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF KANSAS 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: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749091
• 关键词: Adenine; Bacterial Toxins; Biology; Blood; Blood Circulation; Bone Resorption Stimulation; CD14 gene; Cardiovascular Pathology; Cell Culture Techniques; Cell Line; Cells; Chronic Kidney Failure; Cross-Sectional Studies; Data; Defect; Diet; Disease; Endotoxemia; Endotoxins; Etiology; Exhibits; Functional disorder; Gene Expression; Hormones; In Vitro; Inflammation; Inflammatory; Ingestion; Injection of therapeutic agent; Injury; Intestines; Kidney; Kidney Diseases; Link; Lipopolysaccharides; Mediating; Metabolism; Minerals; Mus; Osteoblasts; Osteoclasts; Osteocytes; Outcome; Pathologic; Patients; Pattern; Phenotype; Phosphorus; Physiology; Population; Production; Publishing; Renal function; Reporter; Reporting; Role; Secondary to; Signal Transduction; Source; Staging; Testing; United States National Institutes of Health; Vitamin D; Wild Type Mouse; Work; adverse outcome; bone; fibroblast growth factor 23; in vivo; mouse model; novel; public health relevance; receptor; research study; response; skeletal; translational approach

DESCRIPTION (provided by applicant): Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone that is primarily produced by osteocytes in bone. Circulating levels of this hormone begin to rise at the earliest stages of kidney damage and become markedly elevated with progression of kidney disease. FGF23 not only contributes to mineral and bone abnormalities in patients with CKD, but may also directly induce cardiovascular pathology in this population. Despite substantial evidence linking FGF23 to adverse outcomes, the mechanisms that promote elevated levels of this hormone in CKD remain undefined. Recent reports indicate that patients with CKD exhibit low levels of bacterial endotoxin in their bloodstreams, which may contribute to the inflammatory phenotype that is commonly observed in these patients. While the etiology of this endotoxemia remains unclear, the prevailing hypothesis is that intestinal barrier function is compromised in the setting of kidney injury, allowing endotoxin entry into blood. Interestingly, the pattern of rise for circulating endotoxin levels in CKD mirrors that of FGF23, with modest increments occurring in the early stages of disease and a more dramatic rise in advanced CKD stages. Furthermore, recent observations suggest an independent association between systemic inflammation and FGF23 levels in CKD, possibly implying a pathologic link. It is well-documented that bacterial endotoxin, primarily lipopolysaccharide (LPS), has multiple effects on bone physiology. One of the most established skeletal actions of LPS is a stimulation of bone resorption by promoting osteoclast differentiation via signaling through CD14, a primary LPS co-receptor. Despite a substantial number of studies examining endotoxin effects on osteoblast and osteoclast biology, there is limited published data on LPS effects on osteocytes, the primary cell source for FGF23 production. Preliminary data from our lab suggests that a single injection of LPS in mice stimulates FGF23 gene expression in bone. It remains unclear if this is a direct action on osteocytes in bone or secondary to other systemic actions of LPS. We hypothesize that endotoxemia observed in patients with progressive renal dysfunction contributes to increased FGF23 production by osteocytes in bone in this setting through a CD14-dependent mechanism. We plan to test this hypothesis by: (i) performing both in vitro and in vivo studies to investigate the direct impact of LPS on osteocyte production of FGF23 (Aim 1); (ii) examining the role of CD14 signaling in LPS- mediated FGF23 production by bone by evaluating FGF23 production in CD14-/- mice following LPS injection (Aim 2); and (iii) determining if endotoxemia contributes to the overproduction of FGF23 in CKD through a CD14-dependent mechanism by evaluating FGF23 production by bone from CD14-/- mice following the induction of CKD by adenine ingestion (Aim 3).

描述（由申请人提供）：成纤维细胞生长因子23（FGF 23）是一种磷酸尿和维生素D调节激素，主要由骨中的骨细胞产生。这种激素的循环水平开始在肾损伤的最早阶段上升，并随着肾脏疾病的进展而显著升高。FGF 23不仅导致CKD患者的矿物质和骨异常，而且还可能直接诱导该人群的心血管病理学。尽管有大量证据表明FGF 23与不良结局有关，但促进CKD中这种激素水平升高的机制仍不明确。 最近的报告表明，CKD患者在其血流中表现出低水平的细菌内毒素，这可能有助于在这些患者中常见的炎症表型。虽然这种内毒素血症的病因尚不清楚，但流行的假设是在肾损伤的情况下肠屏障功能受损，从而使内毒素进入血液。有趣的是，CKD中循环内毒素水平升高的模式反映了FGF 23的模式，在疾病的早期阶段出现适度的增加，而在晚期CKD阶段则出现更显著的升高。此外，最近的观察表明，CKD中全身炎症和FGF 23水平之间存在独立关联，可能意味着病理联系。 细菌内毒素，主要是脂多糖（LPS），对骨生理学有多种影响，这是有据可查的。LPS最确定的骨骼作用之一是通过促进破骨细胞分化来刺激骨吸收 通过CD 14（一种主要的LPS共受体）的信号传导。尽管有大量的研究检查内毒素对成骨细胞和破骨细胞生物学的影响，但关于LPS对骨细胞（FGF 23产生的主要细胞来源）的影响的公开数据有限。来自我们实验室的初步数据表明，在小鼠中单次注射LPS刺激骨骼中的FGF 23基因表达。目前尚不清楚这是对骨中骨细胞的直接作用还是继发于LPS的其他全身作用。 我们推测，在进行性肾功能不全患者中观察到的内毒素血症通过CD 14依赖性机制导致骨中骨细胞产生FGF 23增加。我们计划通过以下方式来检验这一假设：（i）进行体外和体内研究，以调查 （ii）通过评估LPS注射后CD 14-/-小鼠中的FGF 23产生来检查CD 14信号传导在LPS介导的由骨产生的FGF 23中的作用（Aim 2）;和（iii）通过评估骨从CD 14-β产生FGF 23，确定内毒素血症是否通过CD 14-β依赖性机制导致CKD中FGF 23的过度产生。在通过腺嘌呤摄入诱导CKD后，对/-小鼠进行了研究（Aim 3）。