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In vivo genetic evidence for klotho‐dependent, fibroblast growth factor 23 (Fgf23) ‐mediated regulation of systemic phosphate homeostasis
Author(s) -
Nakatani Teruyo,
Sarraj Bara,
Ohnishi Mutsuko,
Densmore Michael J.,
Taguchi Takashi,
Goetz Regina,
Mohammadi Moosa,
Lanske Beate,
Razzaque M. Shawkat
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-114397
Subject(s) - klotho , fibroblast growth factor 23 , endocrinology , medicine , fibroblast growth factor , hypophosphatemia , homeostasis , knockout mouse , biology , parathyroid hormone , kidney , calcium , receptor
A major breakthrough in systemic phosphate homeostasis regulation was achieved by the demonstration of strikingly similar physical, morphological, and biochemical phenotypes of fibroblast growth factor 23 ( Fgf23 ) and klotho ablated mice, which led to identification of klotho as an Fgf23 signaling cofactor. Here, we generated Fgf23 and klotho double‐knockout ( Fgf23 −/− /klotho −/− ) mice to test the hypothesis whether Fgf23 has a klotho‐independent function. Fgf23 −/− /klotho −/− mice are viable and have high serum phosphate levels, similar to Fgf23 −/− and klotho −/− single‐knockout mice. In addition, the Fgf23 −/− / klotho −/− mice have increased renal expression of the sodium/phosphate cotransporter NaP i 2a and of 1‐alpha‐hydroxylase concomitant with increased serum levels of 1,25‐dihydroxyvitamin‐D, as also observed in the Fgf23 −/− and klotho mice. Moreover, Fgf23 −/− / klotho −/− mice show soft tissue and vascular calcification, severe muscle wasting, hypogonadism, pulmonary emphysema, distention of intestinal wall, and skin atrophy, all of which are also seen in Fgf23 −/− and klotho −/− mice. Notably, injection of bioactive FGF23 protein into Fgf23 −/− /klotho −/− and klotho −/− mice does not lower serum phosphate, whereas in wild‐type and Fgf23 −/− mice, it reduces serum phosphate. Together, these results provide compelling evidence that Fgf23 does not have a klotho‐independent role in the regulation of systemic phosphate and vitamin D homeostasis.— Nakatani, T., Sarraj, B., Ohnishi, M., Densmore, M. J., Taguchi, T., Goetz, R., Mohammadi, M., Lanske, B., Razzaque, M. S. In vivo genetic evidence for klotho‐dependent, fibroblast growth factor 23 (Fgf23) ‐mediated regulation of systemic phosphate homeostasis. FASEB J. 23, 433–441 (2009)