Comparative effectiveness of therapeutic modalities in X-linked hypophosphatemia

X连锁低磷血症治疗方式的疗效比较

• 批准号: 8592727
• 负责人: Eva S. Liu
• 金额: $ 6.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592727
• 关键词: 1,25 (OH) vitamin D; Adverse effects; Affect; Antibodies; Apoptosis; Attenuated; Blocking Antibodies; Blood Vessels; Bone Density; Bone Diseases; Child; Chondrocytes; Chronic; Chronic Kidney Failure; Defect; Dihydroxycholecalciferols; Dose; Early treatment; Epiphysial cartilage; Excretory function; Femur; Functional disorder; Goals; Growth; Homeostasis; Hormones; Hypophosphatemia; Immunohistochemistry; In Situ Hybridization; Inherited; Intervention; Ions; Kidney; Knockout Mice; Laboratories; Length; Life; Link; MAPK3 gene; Measurement; Measures; Mediating; Minerals; Modality; Modeling; Molecular; Morphology; Mus; Nephrocalcinosis; Pathology; Patients; Phenotype; Phosphorylation; Production; Recommendation; Regimen; Relative (related person); Renal function; Reporting; Resistance; Rickets; Role; Serum; Signal Transduction; Staining method; Stains; Supplementation; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; Vitamin D; Weight; alternative treatment; base; comparative effectiveness; comparative efficacy; gastrointestinal; improved; inhibitor/antagonist; inorganic phosphate; mRNA Expression; mineralization; mouse model; novel; parathyroid hormone-related protein; postnatal; prevent; public health relevance; response; skeletal; skeletal abnormality; tibia; treatment strategy; urinary

DESCRIPTION (provided by applicant): X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 levels, which leads to hypophosphatemia and decreased 1,25-dihydroxyvitamin D production. The current treatment includes daily supplementation with phosphate and 1,25-dihydroxyvitamin D, which are not well tolerated and do not uniformly prevent rickets. We aim to compare the ability of chronic low dose or intermittent high dose 1,25-dihydroxyvitamin D or FGF23 blocking antibodies to normalize mineral ions, modulate mineral regulatory hormones, and prevent rickets in hyp mice (murine model of XLH). We have previously shown that hypophosphatemia impairs hypertrophic chondrocyte apoptosis and leads to rickets. Unlike hyp mice, hypophosphatemic Npt2a null mice with elevated 1,25-dihydroxyvitamin D levels have normal growth plates. Our preliminary results demonstrate that treatment of hypertrophic chondrocytes with 1,25-dihydroxyvitamin D induces basal and phosphate-induced ERK1/2 phosphorylation, which is required for phosphate-mediated hypertrophic chondrocyte apoptosis. These studies suggest a role for 1,25-dihydroxyvitamin D in preventing impaired hypertrophic chondrocyte apoptosis in hypophosphatemic states. We hypothesize that treatment with 1,25-dihydroxyvitamin D will attenuate hypophosphatemia and promote hypertrophic chondrocyte apoptosis. Administration of anti-FGF23 antibodies will improve 1,25- dihydroxyvitamin D production and decrease urinary phosphate excretion, thereby increasing serum phosphate and promoting growth plate maturation. Studies with PTHrP null mice have shown PTH/PTHrP to be an inhibitor of growth plate maturation. Moreover, the growth plates in hyp mice have elevated PTHrP expression. We have demonstrated that treatment of hypertrophic chondrocytes with PTH inhibits ERK1/2 phosphorylation in response to phosphate. All three treatment strategies that we propose should decrease PTH/PTHrP levels by increasing 1,25-dihydroxyvitamin D. In particular, intermittent high dosing of 1,25-dihydroxyvitamin D has been shown to effectively suppress PTH levels. We hypothesize that this decrease in PTH/PTHrP may directly and indirectly improve hypertrophic chondrocyte apoptosis by increasing p-ERK1/2 and phosphate. In specific aim 1, we will compare the ability of chronic low dose or intermittent high dose 1,25-dihydroxyvitamin D or anti-FGF23 antibodies to attenuate mineral ion abnormalities and promote growth in hyp mice. Bone mineral density will be evaluated to examine the effects of these three treatments on mineralization. We also propose to compare the efficacy of the three treatments and identify the molecular basis for the improvement of the growth plate phenotype through histological, in situ hybridization, and immunohistochemical analyses.

描述（由申请人提供）：X连锁的低磷酸血症（XLH）的特征是FGF23水平升高，这导致低磷酸血症并降低了1,25-二羟基羟基胺D产生。当前的治疗方法包括每天补充磷酸盐和1,25-二羟基维生素D，它们的耐受性不佳且不能均匀防止rick鼠。我们的目的是比较慢性低剂量或间歇性高剂量1,25-二羟基维生素D或FGF23阻断抗体归一化矿物离子，调节矿物质调节激素的能力，并防止hyp小鼠中的Rickets（XLH的Murine Model of XLH）。我们先前已经表明，低磷酸血症会损害肥厚的软骨细胞凋亡，并导致rick。与催眠小鼠不同，低磷酸化NPT2A无效小鼠具有升高1,25-二羟基维生素D水平的生长板正常。我们的初步结果表明，用1,25-二羟基维生素D治疗肥厚的软骨细胞D会诱导基底和磷酸盐诱导的ERK1/2磷酸化，这对于磷酸盐介导的肥大性软骨细胞凋亡是必需的。这些研究表明，1,25-二羟基维生素D在防止肥大症状态下肥厚的软骨细胞凋亡受损中的作用。我们假设用1,25-二羟基维生素D治疗将减轻低磷酸血症并促进肥厚的软骨细胞凋亡。抗FGF23抗体的施用将改善1,25-二羟基维生素D产生并降低泌尿磷酸盐排泄，从而增加血清磷酸盐并促进生长板的成熟。 PTHRP无效小鼠的研究表明PTH/PTHRP是生长板成熟的抑制剂。此外，催眠小鼠的生长板的PTHRP表达升高。我们已经证明，用PTH治疗肥厚的软骨细胞会抑制ERK1/2磷酸化对磷酸盐的响应。我们提出的所有三种治疗策略均应通过增加1,25-二羟基维生素D来降低PTH/PTHRP水平。尤其是，已经证明，间歇性高剂量为1,25-二羟基乙胺D，已显示出可有效抑制PTH水平。我们假设PTH/PTHRP的减少可能直接和间接地通过增加P-ERK1/2和磷酸盐来直接和间接改善肥厚的软骨细胞凋亡。在特定的目标1中，我们将比较慢性低剂量或间歇性高剂量1,25-二羟基维生素D或抗FGF23抗体衰减矿物质离子异常并促进催眠小鼠的生长的能力。将评估骨矿物质密度以检查这三种处理对矿化的影响。我们还建议比较三种治疗方法的疗效，并通过组织学，原位杂交和免疫组织化学分析来确定生长板表型改善的分子基础。