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

基本信息

批准号：
10117441
负责人：
Eva S. Liu
金额：
$ 39.36万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10117441
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

项目摘要

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) 是遗传性佝偻病的最常见形式，其特征为 PHEX 突变。这些突变导致 FGF23 血清水平升高，从而导致低磷血症、佝偻病和骨软化症。 FGF23 还抑制维生素 D 1-a-羟化酶 (Cyp27b1)，因此阻断 1,25 二羟基维生素 D (1,25D) 的产生。附着点的病理性矿化（腱骨附着点），称为附着点病，是 XLH 的一种使人衰弱的并发症，会导致严重疼痛以及受影响个体的行动能力受损。常见受影响部位包括髌骨和跟腱附着点。 XLH 附着点病的发病机制尚不清楚。我们之前证明了阿喀琉斯患有 XLH (Hyp) 的小鼠的附着点具有肥大性细胞 (HEC) 的扩增，这些细胞表现出 P14 增强 BMP/IHH 信号传导的异常软骨形成表型。对 Hyp 小鼠的治疗 1,25D 或发育早期 (P2) 的 FGF23 阻断抗体 (FGF23Ab) 同样可以预防附着点病尽管骨中 FGF23 表达显着增加，这表明 1,25D 作用受损是在 Hyp 附着点病中观察到 BMP/IHH 信号增强。在患有 XLH 的小鼠和人类中，1,25D 治疗不能逆转附着点病变，支持了需要早期恢复 1,25D 的假设预防附着点病。小鼠和小鼠中血清 1,25D 水平的增加在 FGF23Ab 启动后减弱患有 XLH 的人类，表明 FGF23Ab 可能无法有效预防 XLH 患者的附着点病。目前尚无关于优化 1,25D 单药治疗或 FGF23Ab 对 XLH 患者附着点病影响的数据。因此，鉴于小鼠和人类对 1,25D 和 FGF23Ab 的反应相似，对激素的研究 XLH 附着点病的调节对于指导未来预防附着点病的临床研究至关重要。初步数据显示 XLH 附着点病变是由 1,25D 作用受损引起的，而不是特定作用 FGF23 或 Hyp 突变的后果。 Aim I 中的研究将检查具有全局缺失的小鼠 Cyp27b1、FGF23 或两者都有或没有 Hyp 突变，以解决损害 1,25D 的假设作用导致 BMP/IHH 信号传导增强和附着点病变。研究还将阐明是否减少了局部 1,25D 作用导致附着点病变。由于我们的数据表明 BMP 信号传导的增加伴随着 Hyp 附着点中 GDF5 表达增强，Aim II 中的研究将确定 GDF5/BMP 的致病作用 Hyp 附着点病发展中的信号传导。研究将确定 WT 中 GDF5 表达的时间进程和 Hyp 的观点。 Hyp 附着点中 GDF5 的消融将确定 GDF5 在 BMP/IHH 激活中的作用 XLH 附着点病变中的信号传导。抑制Hyp小鼠中的BMP信号将表明IHH信号被激活附着点中的 BMP 信号传导和增强的 BMP/IHH 信号传导直接导致附着点病变。采取总之，这些研究将确定 XLH 附着点病变和正常的新型激素和分子调节剂论文发展。他们还将确定设计新疗法的目标，以预防附着点病。