FGF23 Neutralizing Antibody Ameliorates Hypophosphatemia and Impaired FGF Receptor Signaling in Kidneys of HMWFGF2 Transgenic Mice

Abstract

High molecular weight FGF2 transgenic mice (HMWTg) phenocopy the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with phosphate wasting and abnormal fibroblast growth factor (FGF23), fibroblast growth factor receptor (FGFR), Klotho and mitogen activated protein kinases (MAPK) signaling in kidney. In this study, we assessed whether short-term (24 h) in vivo administration of FGF23 neutralizing antibody (FGF23Ab) could rescue hypophosphatemia and impaired FGFR signaling in kidneys of HMWTg male mice. Bone mineral density and bone mineral content in 1-month-old HMWTg mice were significantly reduced compared with Control/VectorTg mice. Serum FGF23 was significantly increased in HMWTg compared with VectorTg. Serum phosphate was significantly reduced in HMWTg and was rescued by FGF23Ab. Serum parathyroid hormone (PTH) was significantly increased in HMWTg but was not reduced by FGF23Ab. 1, 25(OH) D was inappropriately normal in serum of HMWTg and was significantly increased in both Vector and HMWTg by FGF23Ab. Analysis of HMWTg kidneys revealed significantly increased mRNA expression of the FGF23 co-receptor Klotho, transcription factor mRNAs for early growth response-1 transcription factor (Egr-1), and c-fos were all significantly decreased by FGF23Ab. A significant reduction in the phosphate transporter Npt2a mRNA was also observed in HMWTg kidneys, which was increased by FGF23Ab. FGF23Ab reduced p-FGFR1, p-FGFR3, KLOTHO, p-ERK1/2, C-FOS, and increased NPT2A protein in HMWTg kidneys. We conclude that FGF23 blockade rescued hypophosphatemia by regulating FGF23/FGFR downstream signaling in HMWTg kidneys. Furthermore, HMWFGF2 isoforms regulate PTH expression independent of FGF23/FGFR signaling. J. Cell. Physiol. 232: 610-616, 2017. © 2016 Wiley Periodicals, Inc.

FGF23 Neutralizing Antibody Partially Improves Bone Mineralization Defect of HMWFGF2 Isoforms in Transgenic Female Mice

“…Consistent with the studies using Hyp mice that, interestingly, were reported to overexpress HMWFGF2 in osteocytes, we observed that single‐dose treatment with FGF23Ab increased serum Pi and reduced urine Pi excretion in HMWTg mice. This observation is consistent with our recent studies showing that FGF23Ab rescued Pi wasting via increased expression of Npt2a in kidneys of HMWTg male mice . Consistent with our findings FGF23Ab also increased renal expression of Npt2a and decreased fractional excretion of Pi in Hyp mice .…”

“…This observation is consistent with our recent studies showing that FGF23Ab rescued Pi wasting via increased expression of Npt2a in kidneys of HMWTg male mice. (34) Consistent with our findings FGF23Ab also increased renal expression of Npt2a and decreased fractional excretion of Pi in Hyp mice. (23) Our studies show that Npt2a expression in the kidney was increased in HMWTg after single-dose FGF23Ab treatment.…”

X-linked hypophosphatemia and growth

“…It would be of interest to know whether the inhibition of FGF23 activity is useful or not for patients with hypophosphatemic rickets/osteomalacia caused by excessive activity of FGF23 [77]. In this respect there are not many studies in Hyp mouse [78][79][80][81][82][83][84] and only two in humans [85,86].…”

Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice

“…(5) One novel alternative treatment strategy that has emerged is anti-FGF23 antibody (burosumab), which successfully inhibits the action of FGF23 to prevent renal phosphate wasting. (21)(22)(23)(24) Herein, we show that Scl-Ab is another potential treatment strategy that increases phosphate. However, future clinical use of Scl-Ab for XLH would need to be balanced against the risk of adverse cardiac events, which has been reported in postmenopausal osteoporotic women.…”