Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia.
X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
Pharmacological Research Laboratories, Kyowa Hakko Kirin, Tokyo, Japan.
Yukiko
Y
Aono
Yuji
Y
Yamazaki
Junichi
J
Yasutake
Takehisa
T
Kawata
Hisashi
H
Hasegawa
Itaru
I
Urakawa
Toshiro
T
Fujita
Michihito
M
Wada
Takeyoshi
T
Yamashita
Seiji
S
Fukumoto
Takashi
T
Shimada
D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D053098:Familial Hypophosphatemic Rickets / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000652:urine; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000276:immunology*; D040181:Genetic Diseases, X-Linked; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D010018:Osteomalacia / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000652:urine; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D014807:Vitamin D / Q000378:metabolism
D000906:Antibodies; C000717428:Fgf23 protein, mouse; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23