Development of enthesopathy in the mouse model of X-linked hypophosphatemia

X连锁低磷血症小鼠模型附着点病变的进展

• 批准号: 10329988
• 负责人: Eva S. Liu
• 金额: $ 37.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329988
• 关键词: Ablation; Address; Affect; Age; Agonist; Attenuated; Blocking Antibodies; Bone Diseases; CYP27B1 gene; Cartilage; Cells; Chondrocytes; Clinical Research; Clinical Trials; Complication; Data; Development; Dihydroxycholecalciferols; Disease; Enthesopathies; Erinaceidae; Exhibits; Familial hypophosphatemic bone disease; Future; Gene Expression; Genes; Histologic; Hormonal; Hormones; Human; Hypertrophy; Hypophosphatemia; Ihh protein; Impairment; Individual; Inherited; Investigation; Knowledge; Lead; Lentivirus; Ligands; Mechanical Stress; Mediating; Mixed Function Oxygenases; Molecular; Mus; Mutation; Osteomalacia; Pain; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Phenotype; Play; Prevention; Production; Proteoglycan; Regulation; Rickets; Role; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stains; Tendon structure; Time; Vitamin D; Vitamin D3 Receptor; achilles tendon; autocrine; bone; bone morphogenic protein; cartilage development; design; growth differentiation factor 5; hormone regulation; human data; immunoreactivity; improved; mRNA Expression; mineralization; motor impairment; mouse model; muscle stress; mutant mouse model; novel; novel therapeutics; paracrine; patellar tendon; prevent; prospective; response; restoration; scleraxis; smoothened signaling pathway; tendon development; therapeutic target

X-linked hypophosphatemia (XLH) is the most common form of inheritable rickets characterized by mutations in PHEX. These mutations result in elevated serum levels of FGF23, which leads to hypophosphatemia, rickets, and osteomalacia. FGF23 also inhibits vitamin D 1-a-hydroxylase (Cyp27b1), thus blocking 1,25 dihydroxyvitamin D (1,25D) production. Pathologic mineralization of the enthesis (tendon-bone attachment site), referred to as enthesopathy, is a debilitating complication of XLH that causes significant pain and impaired mobility in affected individuals. Common sites affected include the patellar and Achilles entheses. The pathogenesis of XLH enthesopathy is poorly understood. We previously demonstrated that Achilles entheses from mice with XLH (Hyp) have an expansion of hypertrophic appearing cells (HECs) that exhibit an aberrant chondrogenic phenotype with enhanced BMP/IHH signaling by P14. Treatment of Hyp mice with 1,25D or a FGF23 blocking antibody (FGF23Ab) early in development (P2) similarly prevented enthesopathy despite the dramatic increase in FGF23 expression in bone, suggesting impaired 1,25D action underlies the enhanced BMP/IHH signaling observed in Hyp enthesopathy. In both mice and humans with XLH, 1,25D therapy cannot reverse enthesopathy, supporting the hypothesis that early restoration of 1,25D is needed to prevent enthesopathy. The increase in serum 1,25D levels wane post-initiation of FGF23Ab in both mice and humans with XLH, suggesting FGF23Ab may not be effective in preventing enthesopathy in XLH patients. There is no data on the effects of optimized 1,25D monotherapy or FGF23Ab on enthesopathy in XLH patients. Therefore, given the similar responses of mice and humans to 1,25D and FGF23Ab, studies on the hormonal regulation of XLH enthesopathy are essential to guiding future clinical studies on enthesopathy prevention. Preliminary data show that XLH enthesopathy results from impaired 1,25D action, not actions specific to FGF23 or consequences of the Hyp mutation. Studies in Aim I will examine mice with global deletions of Cyp27b1, FGF23, or both with or without the Hyp mutation to address the hypothesis that impaired 1,25D action leads to enhanced BMP/IHH signaling and enthesopathy. Studies will also elucidate if decreased local 1,25D action leads to enthesopathy. Since our data demonstrates increased BMP signaling is accompanied by enhanced GDF5 expression in Hyp entheses, studies in Aim II will identify a pathogenic role for GDF5/BMP signaling in Hyp enthesopathy development. Studies will determine the time course of GDF5 expression in WT and Hyp entheses. Ablation of GDF5 in Hyp entheses will define the role of GDF5 in the activation of BMP/IHH signaling in XLH enthesopathy. Inhibition of BMP signaling in Hyp mice will show that IHH signaling is activated by BMP signaling in entheses and enhanced BMP/IHH signaling directly leads to enthesopathy. Taken together, these studies will identify novel hormonal and molecular regulators of XLH enthesopathy and normal enthesis development. They will also identify targets for the design of new therapies to prevent enthesopathy.

X连锁低磷血症（XLH）是最常见的遗传性rick鼠，其特征是 PHEX中的突变。这些突变导致血清水平升高FGF23，这导致 低磷血症，rick骨和骨质乳酸。 FGF23还抑制维生素D 1-A-羟化酶（CYP27B1），因此 阻止1,25个二羟基维生素D（1,25d）生产。肌腱骨的病理矿化（肌腱骨） 附件位点），称为肠病，是XLH的令人衰弱的并发症，会引起严重的疼痛 受影响个体的流动性障碍。受影响的普通部位包括tell骨和致命弱点。 XLH肠病的发病机理知之甚少。我们以前证明了阿喀琉斯 来自XLH（hyp）小鼠的肠胃肠膨胀有肥厚的出现细胞（HEC），表现出 p14的异常软骨表型具有增强的BMP/IHH信号传导。用 开发早期（P2）的1,25D或FGF23阻断抗体（FGF23AB）类似地阻止了肠病 尽管骨骼中FGF23表达的表达急剧增加，这表明1,25D动作受损是基础 在催眠性疾病中观察到的增强的BMP/IHH信号传导。在带有XLH的小鼠和人类中，1,25d 治疗不能逆转肠病，支持以下假设：需要早期恢复1,25D 预防肠病。在小鼠和 具有XLH的人，表明FGF23AB可能无法有效预防XLH患者的肠病。 没有关于优化的1,25D单一疗法或FGF23AB对XLH患者肠病的影响的数据。 因此，鉴于小鼠和人类对1,25D和FGF23AB的相似反应，对激素的研究 XLH肠病的调节对于指导预防肠病的未来临床研究至关重要。 初步数据表明，XLH Enthesopathy是由于1,25D动作受损而不是特定动作的 对FGF23或催眠突变的后果。目的研究我将检查小鼠的全球删除 CYP27B1，FGF23或两者都有或没有催眠突变，以解决1,25D损害的假设 动作会导致增强的BMP/IHH信号传导和肠病。研究还将阐明如果局部减少 1,25D行动导致肠病。由于我们的数据表明增加的BMP信号伴随着 增强的GDF5表达在催眠中，AIM II的研究将确定GDF5/BMP的致病作用 催眠诱因发育中的信号传导。研究将确定WT中GDF5表达的时间过程 和催眠。 GDF5在催眠剂中的消融将定义GDF5在BMP/IHH激活中的作用 XLH肠病中的信号传导。催眠小鼠中BMP信号传导的抑制作用将表明IHH信号被激活 通过恩斯群中的BMP信号传导和增强的BMP/IHH信号传导直接导致肠病。拍摄 总之，这些研究将确定XLH肠病和正常的新型激素和分子调节剂 ENTEMES发展。他们还将确定设计新疗法的靶标，以防止肠病。