Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype - PubMed (original) (raw)
. 2009 Jan;296(1):E79-88.
doi: 10.1152/ajpendo.90539.2008. Epub 2008 Nov 4.
Affiliations
- PMID: 18984852
- DOI: 10.1152/ajpendo.90539.2008
Free article
Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype
Xiuying Bai et al. Am J Physiol Endocrinol Metab. 2009 Jan.
Free article
Abstract
Transgenic mice overexpressing fibroblast growth factor (FGF23) (R176Q) (F(Tg)) exhibit biochemical {hypophosphatemia, phosphaturia, abnormal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] metabolism} and skeletal (rickets and osteomalacia) abnormalities attributable to FGF23 action. In vitro studies now implicate the aging-related factor Klotho in the signaling mechanism of FGF23. In this study, we used a mouse genetic approach to validate in vivo the pivotal role of Klotho in the metabolic and skeletal derangements associated with FGF23 (R176Q) overexpression. To this end, we crossed mice heterozygous for the hypomorphic Klotho allele (Kl(+/-)) to F(Tg) mice and obtained F(Tg) transgenic mice homozygous for the Kl-hypomorphic allele (F(Tg)/Kl(-/-)). Mice were killed on postnatal day 50, and serum and tissues were procured for analysis and comparison with F(Tg), wild-type, and Kl(-/-) controls. From 4 wk onward, F(Tg)/Kl(-/-) mice were clearly distinguishable from F(Tg) mice and exhibited a striking phenotypic resemblance to the Kl(-/-) controls. Serum analysis for calcium, phosphorus, parathyroid hormone, 1,25(OH)(2)D(3), and alkaline phosphatase activity confirmed the biochemical similarity between the F(Tg)/Kl(-/-) and Kl(-/-) mice and their distinctness from the F(Tg) controls. The characteristic skeletal changes associated with FGF23 (R176Q) overexpression were also dramatically reversed by the absence of Klotho. Hence the wide, unmineralized growth plates and the osteomalacic abnormalities apparent in trabecular and cortical bone were completely reversed in the F(Tg)/Kl(-/-) mice. Nevertheless, independent actions of Klotho on bone were suggested as manifested by alterations in mineralized bone, and in cortical bone volume which were observed in both the Kl(-/-) and F(Tr)/Kl(-/-) mutants. In summary, our findings substantiate in vivo the essential role of Klotho in the mechanism of action of FGF23 in view of the fact that Klotho ablation converts the biochemical and skeletal manifestations resulting from FGF23 overexpression to a phenotype consistent with Klotho deficiency.
Similar articles
- Deletion of PTH rescues skeletal abnormalities and high osteopontin levels in Klotho-/- mice.
Yuan Q, Sato T, Densmore M, Saito H, Schüler C, Erben RG, Lanske B. Yuan Q, et al. PLoS Genet. 2012;8(5):e1002726. doi: 10.1371/journal.pgen.1002726. Epub 2012 May 17. PLoS Genet. 2012. PMID: 22615584 Free PMC article. - Soluble Klotho causes hypomineralization in Klotho-deficient mice.
Minamizaki T, Konishi Y, Sakurai K, Yoshioka H, Aubin JE, Kozai K, Yoshiko Y. Minamizaki T, et al. J Endocrinol. 2018 Jun;237(3):285-300. doi: 10.1530/JOE-17-0683. Epub 2018 Apr 9. J Endocrinol. 2018. PMID: 29632215 - Klotho expression in long bones regulates FGF23 production during renal failure.
Kaludjerovic J, Komaba H, Sato T, Erben RG, Baron R, Olauson H, Larsson TE, Lanske B. Kaludjerovic J, et al. FASEB J. 2017 May;31(5):2050-2064. doi: 10.1096/fj.201601036R. Epub 2017 Feb 9. FASEB J. 2017. PMID: 28183805 - [Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis].
Nabeshima Y. Nabeshima Y. Clin Calcium. 2008 Jul;18(7):923-34. Clin Calcium. 2008. PMID: 18591743 Review. Japanese. - FGF23-FGF Receptor/Klotho Pathway as a New Drug Target for Disorders of Bone and Mineral Metabolism.
Fukumoto S. Fukumoto S. Calcif Tissue Int. 2016 Apr;98(4):334-40. doi: 10.1007/s00223-015-0029-y. Epub 2015 Jul 1. Calcif Tissue Int. 2016. PMID: 26126937 Review.
Cited by
- Infections and Autoimmunity-The Immune System and Vitamin D: A Systematic Review.
Wimalawansa SJ. Wimalawansa SJ. Nutrients. 2023 Sep 2;15(17):3842. doi: 10.3390/nu15173842. Nutrients. 2023. PMID: 37686873 Free PMC article. Review. - FGF23 and klotho at the intersection of kidney and cardiovascular disease.
Edmonston D, Grabner A, Wolf M. Edmonston D, et al. Nat Rev Cardiol. 2024 Jan;21(1):11-24. doi: 10.1038/s41569-023-00903-0. Epub 2023 Jul 13. Nat Rev Cardiol. 2024. PMID: 37443358 Review. - Physiological Basis for Using Vitamin D to Improve Health.
Wimalawansa SJ. Wimalawansa SJ. Biomedicines. 2023 May 26;11(6):1542. doi: 10.3390/biomedicines11061542. Biomedicines. 2023. PMID: 37371637 Free PMC article. - FGF23 and its role in X-linked hypophosphatemia-related morbidity.
Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, de Lucas Collantes C, Schnabel D, Jandhyala R, Mäkitie O. Beck-Nielsen SS, et al. Orphanet J Rare Dis. 2019 Feb 26;14(1):58. doi: 10.1186/s13023-019-1014-8. Orphanet J Rare Dis. 2019. PMID: 30808384 Free PMC article. Review. - Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy.
McKenna MJ, Martin-Grace J, Crowley R, Twomey PJ, Kilbane MT. McKenna MJ, et al. J Bone Miner Metab. 2019 Jul;37(4):685-693. doi: 10.1007/s00774-018-0957-5. Epub 2018 Sep 20. J Bone Miner Metab. 2019. PMID: 30238432
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous