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Circulating αKlotho influences phosphate handling by controlling FGF23 production
Rosamund C. Smith, … , Matthew D. Breyer, Kenneth E. White
Rosamund C. Smith, … , Matthew D. Breyer, Kenneth E. White
Published November 26, 2012
Citation Information: J Clin Invest. 2012;122(12):4710-4715. https://doi.org/10.1172/JCI64986.
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Brief Report

Circulating αKlotho influences phosphate handling by controlling FGF23 production

Abstract

The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization.

Authors

Rosamund C. Smith, Linda M. O’Bryan, Emily G. Farrow, Lelia J. Summers, Erica L. Clinkenbeard, Jessica L. Roberts, Taryn A. Cass, Joy Saha, Carol Broderick, Y. Linda Ma, Qing Qiang Zeng, Alexei Kharitonenkov, Jonathan M. Wilson, Qianxu Guo, Haijun Sun, Matthew R. Allen, David B. Burr, Matthew D. Breyer, Kenneth E. White

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Ectopic expression of αKlotho as an explanation for high FGF23 levels in the circulating αKlotho over-expression model.

Submitter: Nobuaki Ito | nobitotky@gmail.com

Authors: Gerald J. Atkins, and David M. Findlay

Centre for Orthopaedic & Trauma Research, The University of Adelaide

Published December 14, 2012

Smith et al. (1) postulate that circulating αKlotho (cKL) stimulates the production of the phosphaturic hormone, Fibroblast Growth Factor 23 (FGF23) by a novel endocrine feedback mechanism. This proposal is based on the resulting high serum FGF23 levels in mice infected with an adeno-associated virus producing cKL (AAV-cKL). cKL is the cleaved form of membrane-bound αKlotho (mKL), which is mainly expressed in the kidney tubule (2) forming a co-receptor for FGF23 in concert with canonical Fibroblast growth factor receptors (FGFRs). However, the authors’ interpretation is difficult to reconcile with the αKlotho deficient mouse, which displayed high serum FGF23 levels, apparently in a physiological feedback response to high serum inorganic phosphate (Pi) and 1,25-dihydroxy vitamin D (1,25D) (3).

An alternative interpretation is possible. cKL lacks the transmembrane domain of αKlotho but retains the FGF23 binding site and could potentially function like mKL if expressed by the same cells producing FGFR and FGF23. The last author of the current article previously reported FGFR gain-of-function in humans causes osteoglophonic dysplasia accompanied by hypophosphatemic rickets, with high serum FGF23 (4). Additional in vivo and in vitro evidence suggests that FGFR signals directly stimulate FGF23 production (5, 6). Taken together, these data support the principle that in AAV-cKL injected mice, FGF23 could stimulate its own production in osteoblasts/osteocytes by binding a cKL-FGFR complex, due to the ectopic expression of cKL in bone. This short-circuited stimulation of FGF23 could overwhelm the physiological regulation of FGF23 by Pi and 1,25D.

The current study was prompted by a previous report of a rare human condition caused by balanced translocation between chromosome 9 and 13: t(9,13)(q21.13:q13.1) with a breakpoint 50 kb upstream of the start codon of αKLOTHO, leading to a rachitic phenotype with low serum Pi and 1,25D and dramatically up-regulated serum FGF23 and cKL (7), phenocopying the AAV-cKL mouse (1). The authors proposed that the overproduction of αKlotho, to which they ascribed the phenotype, was due to a putative enhancer region on chromosome 13 acting in cis with chromosome 9 including the αKLOTHO gene. We propose that a similar ectopic expression of αKlotho was induced in this patient, as described above for the AAV-cKL mouse. It is noteworthy that translocation in a number of other genetic conditions results in loss of organ-specific expression (8).

Therefore, further work will be required to determine whether cKL is able to act as a humoral factor or a circulating receptor.

References

  1. Smith, R.C., O'Bryan, L.M., Farrow, E.G., Summers, L.J., Clinkenbeard, E.L., Roberts, J.L., Cass, T.A., Saha, J., Broderick, C., Ma, Y.L., et al. 2012. Circulating alphaKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest 122:4710-4715.
  2. Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. 1997. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45-51.
  3. Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., and Yamashita, T. 2006. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770-774.
  4. White, K.E., Cabral, J.M., Davis, S.I., Fishburn, T., Evans, W.E., Ichikawa, S., Fields, J., Yu, X., Shaw, N.J., McLellan, N.J., et al. 2005. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76:361-367.
  5. Martin, A., Liu, S., David, V., Li, H., Karydis, A., Feng, J.Q., and Quarles, L.D. 2011. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25:2551-2562.
  6. Wohrle, S., Bonny, O., Beluch, N., Gaulis, S., Stamm, C., Scheibler, M., Muller, M., Kinzel, B., Thuery, A., Brueggen, J., et al. 2011. FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res 26:2486-2497.
  7. Brownstein, C.A., Adler, F., Nelson-Williams, C., Iijima, J., Li, P., Imura, A., Nabeshima, Y., Reyes-Mugica, M., Carpenter, T.O., and Lifton, R.P. 2008. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A 105:3455-3460.
  8. Kleinjan, D.J., and van Heyningen, V. 1998. Position effect in human genetic disease. Hum Mol Genet 7:1611-1618.

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