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J Bone Miner Res ; 28(4): 899-911, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23129509

ABSTRACT

Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases.


Subject(s)
Fibroblast Growth Factors/metabolism , Phenylurea Compounds/pharmacology , Pyrimidines/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Rickets, Hypophosphatemic/metabolism , Signal Transduction/drug effects , Animals , Body Weight/drug effects , Bone Development/drug effects , Extracellular Matrix Proteins/deficiency , Extracellular Matrix Proteins/metabolism , Femur/drug effects , Femur/pathology , Fibroblast Growth Factor-23 , Growth Plate/drug effects , Growth Plate/pathology , Homeostasis/drug effects , Ions , Kidney/drug effects , Kidney/metabolism , Mice, Inbred C57BL , Minerals/metabolism , Phenylurea Compounds/therapeutic use , Pyrimidines/therapeutic use , Receptors, Fibroblast Growth Factor/metabolism , Rickets, Hypophosphatemic/drug therapy , Rickets, Hypophosphatemic/pathology , Tail/anatomy & histology , Vitamin D/analogs & derivatives , Vitamin D/biosynthesis
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