A PAI-1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D-resistant rickets model mouse

被引：0

作者：

Qian, Cheng ^{[1
]}

Ito, Nobuaki ^{[2
]}

Tsuji, Kunikazu ^{[1
]}

Sato, Shingo ^{[1
]}

Kikuchi, Katsushi ^{[1
]}

Yoshii, Toshitaka ^{[1
]}

Miyata, Toshio ^{[3
]}

Asou, Yoshinori ^{[1
,4
,5
]}

机构：

[1] Tokyo Med & Dent Univ, Dept Orthoped Surg, Tokyo, Japan

[2] Univ Tokyo Hosp, Div Nephrol & Endocrinol, Tokyo, Japan

[3] Tohoku Univ, United Ctr Adv Res & Translat Med, Sendai, Japan

[4] Shanghai Univ, China Japan Friendship Inst Med, Shanghai, Peoples R China

[5] Tokyo Med & Dent Univ, Dept Orthoped Surg, 1-5-45 Yushima Bunkyo Ku, Tokyo 1138519, Japan

来源：

FEBS OPEN BIO | 2024年 / 14卷 / 02期

关键词：

fibroblast growth factor 23; Hyp mouse; hypophosphatemia; plasminogen activator inhibitor-1 antagonist; vitamin D-resistant rickets and osteomalacia; PLASMINOGEN-ACTIVATOR INHIBITOR-1; PEX GENE; EXPRESSION; KLOTHO; GROWTH;

D O I：

10.1002/2211-5463.13745

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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<middle dot>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-1 alpha-hydroxylase protein encoded by Cyp27b1 mRNA in the kidney was suppressed in Hyp mice, and treatment with 10 mg<middle dot>kg(-1) of TM5614 normalized the expression of 25-hydroxyvitamin D-1 alpha-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.

引用

页码：290 / 299

页数：10