Congenital fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets/osteomalacia is a rare bone metabolism disorder characterized by hypophosphatemia and caused by genetic abnormalities that result in excessive secretion of FGF23. Hyp mice are a model of X-linked hypophosphatemia (XLH) caused by deletion of the PHEX gene and excessive production of FGF23. The purpose of this study was to investigate the potential of TM5614 as a therapeutic agent for the treatment of congenital FGF23-related hypophosphatemic rickets and osteomalacia in humans by administering TM5614 to Hyp mice and examining its curative effect on hypophosphatemia. After a single oral administration of TM5614 10 mg·kg⁻¹ to female Hyp mice starting at 17 weeks of age, the serum phosphate concentration increased with a peak at 6 h after administration. ELISA confirmed that TM5614 administration decreased the intact FGF23 concentration in the blood. Expression of 25-hydroxyvitamin D-1α-hydroxylase protein encoded by Cyp27b1 mRNA in the kidney was suppressed in Hyp mice, and treatment with 10 mg·kg⁻¹ of TM5614 normalized the expression of 25-hydroxyvitamin D-1α-hydroxylase protein and Cyp27b1 mRNA in the kidneys of these mice. Our data indicate that oral administration of TM5614 ameliorates hypophosphatemia in Hyp mice, suggesting that TM5614 may be an effective treatment for congenital FGF23-related hypophosphatemic rickets and osteomalacia.

中文翻译：

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PAI-1 拮抗剂可改善 Hyp 维生素 D 抗性佝偻病模型小鼠的低磷血症

先天性成纤维细胞生长因子 23 (FGF23) 相关的低磷血症性佝偻病/骨软化症是一种罕见的骨代谢疾病，其特征是低磷血症，由导致 FGF23 过度分泌的遗传异常引起。Hyp小鼠是由PHEX基因缺失和 FGF23 过量产生引起的 X 连锁低磷血症 (XLH) 模型。本研究的目的是通过给Hyp小鼠施用TM5614并检查其对低磷血症的疗效，探讨TM5614作为治疗剂治疗人类先天性FGF23相关的低磷血症性佝偻病和骨软化症的潜力。雌性Hyp小鼠从17周龄开始单次口服TM5614 10 mg·kg ^-1后，血清磷酸盐浓度升高，并在给药后6 h达到峰值。 ELISA 证实 TM5614 给药降低了血液中完整 FGF23 的浓度。Hyp小鼠肾脏中由Cyp27b1 mRNA编码的25-羟基维生素D-1α-羟化酶蛋白的表达受到抑制，并且用10 mg·kg ^-1 TM5614处理使25-羟基维生素D-1α-羟化酶蛋白和Cyp27b1的表达正常化这些小鼠肾脏中的 mRNA。我们的数据表明，口服 TM5614 可改善Hyp小鼠的低磷血症，表明 TM5614 可能是治疗先天性 FGF23 相关的低磷血症性佝偻病和骨软化症的有效治疗方法。