The role of DMP1 in FGF23-induced hypophosphatemia

DMP1 在 FGF23 诱导的低磷血症中的作用

• 批准号: 10596626
• 负责人: Aline C Martin
• 金额: $ 63.79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596626
• 关键词: Animals; Antibodies; Blocking Antibodies; Bone Growth; Bone Pain; Cells; Data; Defect; Dentin; Diet; Disease; Endopeptidases; Equilibrium; Excretory function; Familial hypophosphatemic bone disease; Fibroblast Growth Factor Receptors; Fracture; Functional disorder; Genes; Genetic; Goals; Growth; Homeostasis; Hormones; Human; Hypophosphatemia; Impairment; In Vitro; Inherited; Injections; Intake; Intestines; Kidney; Kidney Transplantation; Link; Mediating; Metabolism; Minerals; Modification; Mus; Mutant Strains Mice; Mutation; Osteoblasts; Osteocytes; Osteomalacia; Pathogenesis; Phenotype; Physiologic calcification; Production; Productivity; Protein Deficiency; Proteins; Recurrence; Regulation; Renal function; Reporting; Repression; Role; Serum; Signal Transduction; Supplementation; Testing; Time; Tissues; Transplant Recipients; Tubular formation; Universities; Wild Type Mouse; Work; absorption; autosome; bone; bone loss; defined contribution; dentin matrix protein 1; dietary; fibroblast growth factor 23; improved; improved outcome; in vivo; innovation; inorganic phosphate; mineralization; mutant; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; protein function; response; skeletal; soft tissue; therapeutic target; urinary; wasting

PROJECT SUMMARY Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone. Hypophosphatemic rickets disorders, such as X-linked hypophosphatemia (XLH) and autosomal recessive hypophosphatemic rickets (ARHR), are associated with FGF23 excess, impaired skeletal growth and osteomalacia leading to debilitating bone pain and fractures. New therapy consisting in FGF23 antibody injections to increase serum phosphate (Pi) levels in XLH improves bone growth and mineralization. However, further studies are needed to determine if this strategy is efficacious in the long term and in other diseases associated with FGF23 excess, including ARHR. XLH and ARHR type I are respectively caused by inactivating mutations of Pi regulating gene with homologies to endopeptidase X-linked (PHEX) and dentin matrix protein (DMP1) that work in concert to regulate FGF23 production. In preliminary data for this project, we show that (1) FGF23 excess and hypophosphatemia contribute to the bone defects in mice with ARHR, (2) excess FGF23 and parathryroid hormone are not solely responsible for renal Pi wasting, (3) DMP1 directly stimulates Pi reabsorption in the kidney, (4) PHEX and DMP1 are expressed in renal tubular cells where Pi reabsorption occurs, and (5) loss of kidney PHEX induces phosphaturia and bone loss despite increased DMP1 and low FGF23 levels. The goal of this project is to investigate the pathogenesis of hypophosphatemia induced by DMP1 deficiency. In Aim 1, we will define the contribution of FGF23 excess and hypophosphatemia to impaired bone mineralization in mice with ARHR. We will use normal and high dietary Pi administration, and genetic deletion of Fgf23 in wild- type (WT) and Dmp1KO to assess modifications of bone and mineral metabolism in mice and cultured primary osteoblasts over time. In Aim 2, we will establish the role of DMP1 in stimulating Pi reabsorption by antagonizing FGF23-FGFR1 signaling in the kidney. We will use normal and high dietary Pi administration, and genetic overexpression of Fgf23 or deletion of Fgfr1, in WT mice and in animals with genetic overexpression of Dmp1 (Dmp1TG). We will assess bone and mineral metabolism, Pi intake and excretion, kidney function and FGFR1 activation in the kidney, in presence of elevated FGF23 and DMP1 levels. Finally, in Aim 3, we will investigate the contribution of kidney DMP1 deficiency to the pathophysiology of ARHR and XLH by performing kidney transplants between Dmp1TG and Dmp1KO and between WT, Hyp and Dmp1TG donor and recipient mice. We will establish whether kidney-expressed DMP1 is required to fully correct hypophosphatemia in mice with ARHR, and if loss of kidney PHEX function is sufficient to induce hyperphosphaturia and bone loss despite elevated DMP1 and low FGF23 levels. This will demonstrate a key functional interaction between PHEX and DMP1 in the kidney. These innovative aims are supported by a productive collaborative team at Northwestern University that will further develop our understanding of DMP1, FGF23 and Pi function, and ultimately help to develop novel therapies to improve outcomes in diseases associated with altered Pi balance.

项目摘要 成纤维细胞生长因子23（FGF 23）是由骨产生的磷酸尿激素。低血磷佝偻病 疾病，如X连锁低磷酸盐血症（XLH）和常染色体隐性低磷酸盐血症佝偻病 （ARHR），与FGF 23过量、骨骼生长受损和骨软化相关，导致衰弱 骨痛和骨折。新疗法包括FGF 23抗体注射以增加血清磷酸盐（Pi） XLH水平改善骨生长和矿化。然而，还需要进一步的研究来确定， 该策略在长期和其它与FGF 23过量相关的疾病（包括ARHR）中有效。 XLH和ARHR I型分别由具有同源性的Pi调节基因失活突变引起 内肽酶X-连锁（PHEX）和牙本质基质蛋白（DMP 1），它们共同调节FGF 23 生产在该项目的初步数据中，我们表明（1）FGF 23过量和低磷酸盐血症 在ARHR小鼠中，（2）过量的FGF 23和类胡萝卜素不仅是ARHR小鼠骨缺损的原因， （3）DMP 1直接刺激肾脏中的Pi重吸收，（4）PHEX和DMP 1 在发生Pi重吸收的肾小管细胞中表达，和（5）肾PHEX的丧失诱导 磷酸尿和骨丢失，尽管增加的DMP 1和低FGF 23水平。该项目的目标是 探讨DMP 1缺乏致低磷血症的发病机制。 在目标1中，我们将明确FGF 23过量和低磷酸盐血症对骨矿化受损的作用 在ARHR小鼠中。我们将使用正常和高膳食Pi施用，并在野生型中基因缺失Fgf 23。 型（WT）和Dmp 1 KO，以评估小鼠骨和矿物质代谢的改变，并培养原代 随着时间的推移。在目的2中，我们将建立DMP 1在刺激Pi重吸收中的作用， 肾脏中的FGF 23-FGFR 1信号传导。我们将使用正常和高饮食Pi管理，并遗传 WT小鼠和Dmp 1基因过表达动物中Fgf 23过表达或Fgfr 1缺失 （Dmp1TG）。我们将评估骨和矿物质代谢、Pi摄入和排泄、肾功能和FGFR 1 在存在升高的FGF 23和DMP 1水平的情况下，肾脏中的活化。最后，在目标3中，我们将研究 肾DMP 1缺乏通过肾移植对ARHR和XLH的病理生理学的贡献 Dmp 1 TG和Dmp 1 KO之间以及WT、Hyp和Dmp 1 TG供体和受体小鼠之间的移植。我们 将确定肾脏表达的DMP 1是否需要完全纠正ARHR小鼠的低磷酸盐血症， 如果肾PHEX功能丧失足以诱导高磷酸盐尿和骨丢失，尽管升高 DMP 1和低FGF 23水平。这将证明PHEX和DMP 1之间的关键功能相互作用， 肾这些创新目标得到了西北大学一个富有成效的合作团队的支持， 将进一步发展我们对DMP 1，FGF 23和Pi功能的理解，并最终有助于开发新的 改善与Pi平衡改变相关的疾病的治疗结果。