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: 10548844
• 负责人: Eva S. Liu
• 金额: $ 37.62万
• 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/10548844
• 关键词: Ablation; Address; Affect; Age; Agonist; Attenuated; Blocking Antibodies; Bone Diseases; Bone Morphogenetic Proteins; 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; Impairment; Individual; Inherited; Investigation; Knowledge; Lentivirus; Ligands; Mechanical Stress; Mediating; 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; 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）是最常见的遗传性佝偻病，其特征是 PHEX中的突变。这些突变导致FGF 23的血清水平升高，这导致 低磷酸盐血症佝偻病和骨软化症FGF 23还抑制维生素D1-α-羟化酶（Cyp 27 b1），因此 阻断1，25二羟维生素D（1，25 D）的产生。附着点（腱-骨）的病理矿化 附着部位），称为附着点病，是XLH的一种使人衰弱的并发症，可引起明显的疼痛 以及受影响个体的活动能力受损。受影响的常见部位包括髌骨和跟腱。 XLH末端病的发病机制知之甚少。我们之前证明过阿基里斯 来自患有XLH（Hyp）的小鼠的附着点具有肥大外观细胞（HEC）的扩增， 通过P14增强BMP/IHH信号传导的异常软骨形成表型。用以下处理Hyp小鼠 1，25 D或FGF 23阻断抗体（FGF 23 Ab）在发育早期（P2）类似地预防了末端病。 尽管骨中FGF 23表达显著增加，但提示受损的1，25 D作用是骨损伤的基础。 在Hyp endothesopathy中观察到增强的BMP/IHH信号传导。在患有XLH的小鼠和人类中，1，25 D 治疗不能逆转末端病，支持需要早期恢复1，25 D的假设， 预防末端病。在小鼠和小鼠中，血清1，25 D水平的增加在开始FGF 23 Ab后减弱， 提示FGF 23 Ab可能不能有效预防XLH患者的末端病。 没有关于优化的1，25 D单药治疗或FGF 23 Ab对XLH患者的末端病的影响的数据。 因此，考虑到小鼠和人类对1，25 D和FGF 23 Ab的相似反应，关于激素调节的研究是必要的。 XLH末端病的调节对于指导未来的末端病预防的临床研究是必不可少的。 初步数据表明，XLH末端病是由受损的1，25 D作用引起的，而不是特定的作用 FGF 23或Hyp突变的后果。目标I中的研究将检查具有以下基因的整体缺失的小鼠： Cyp 27 b1、FGF 23或两者，有或没有Hyp突变，以解决1，25 D受损的假设 作用导致增强的BMP/IHH信号传导和末端病。研究还将阐明，如果局部 1，25 D作用导致末端病。由于我们的数据表明BMP信号的增加伴随着 由于Hyp附着点中GDF 5表达增强，Aim II中的研究将确定GDF 5/BMP的致病作用 Hyp endothesopathy发展的信号传导。研究将确定WT中GDF 5表达的时间过程， 和hypetheses。在Hyp附着点中GDF 5的消融将确定GDF 5在BMP/IHH激活中的作用。 XLH末端病中的信号传导。在Hyp小鼠中BMP信号传导的抑制将显示IHH信号传导被激活 BMP/IHH信号通路的增强直接导致附着点病变。采取 总之，这些研究将确定新的激素和分子调节XLH末端病和正常 附着点发育他们还将确定新疗法的设计目标，以预防末端病。