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Erben: Fgf-23 and Klotho - mineral homeostasis - aging

Klotho and fibroblast growth factor-23 (Fgf-23) have recently been identified as essential factors in the regulation of phosphate homeostasis and of aging. The transmembrane form of Klotho acts as co-receptor for Fgf-23. Therefore, deficiency in either Fgf-23 or Klotho has similar biological consequences. Klotho (Klotho^-/-) and Fgf-23 deficient (Fgf-23^-/-) mice are characterized by osteomalacia, hypercalcemia, hyperphosphatemia, elevated circulating vitamin D hormone, hypoglycemia, increased peripheral insulin sensitivity, shortened life span, vascular calcifications, lung emphysema, growth hormone deficiency, and organ atrophies. Ablation of vitamin D signaling in vitamin D receptor or 1α-hydroxylase deficient mice rescues most of the abnormalities found in Klotho^-/- and Fgf-23^-/- mice. Therefore, the major physiological function of Fgf-23 is probably the suppression of renal 1α-hydroxylase activity, the most important enzyme in the vitamin D activation pathway. However, several lines of evidence suggest that Fgf-23 and Klotho may have additional, vitamin D independent, molecular roles in the regulation of bone metabolism, of parathyroid hormone secretion, of peripheral insulin sensitivity, of oxidative stress, and of the physiological aging process. By employing different genetically engineered mouse models, the current proposal aims to shed additional light on the question whether the sole physiological function of Fgf23 and Klotho is the regulation of renal 1α-hydroxylase activity, or whether these factors have vitamin D independent effects in the regulation of aging, oxidative stress, bone and mineral homeostasis, and peripheral insulin sensitivity. The proposed experiments will significantly advance our knowledge about the physiological and pathophysiological role of Fgf-23 and Klotho in mineral homeostasis, in aging, in the regulation of peripheral insulin sensitivity, and in the protection against oxidative stress. An improved understanding of these mechanisms may lead to new insights into the pathophysiology and treatment of bone diseases, diseases of mineral homeostasis, diabetes, or cardiovascular diseases.

Publication List

1. Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG (2003) Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J 17:509-511. IF 6.79
2. Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Jüppner H, Lanske B (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23:421-32. IF 3.69
3. Erben RG, Mayer D, Weber K, Jonsson K, Jüppner H, Lanske B (2005) Overexpression of human PHEX under the human β–actin promoter does not fully rescue the Hyp mouse phenotype. J Bone Miner Res 20:1149-1160. IF 6.00
4. Sitara D, Razzaque MS, St-Arnaud R, Taguchi T, Erben RG, Lanske B (2006) Ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23 null animals. Am J Pathol 169:2161-70. IF 5.49
5. Hesse M, Fröhlich LF, Zeitz U, Lanske B, Erben RG (2007) Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biology 26:75-84. Epub 2006 Oct 20. IF 3.69
6. Sitara D, Razzaque MS, Bergwitz C, Taguchi T, Jüppner H, Erben RG, Lanske B (2008) Genetic evidence of serum phosphate-independent function of FGF-23 on bone. PLOS Genetics 4:e1000154 (8 Aug 2008). IF 8.72
7. DeLuca S, Sitara D, Kang K, Marsell R, Jonsson K, Taguchi T, Erben RG, Razzaque MS, Lanske B (2008) Amelioration of the premature aging-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23. J Pathol 216:345-55. IF 5.42
8. Schneider M, Mayer-Rönne B, Dahlhoff M, Proell V, Weber K, Wolf E, Erben RG (2009) High cortical bone mass phenotype in betacellulin transgenic mice is EGFR-dependent. J Bone Miner Res 24:455-67. IF 6.00
9. Weber K, Zeitz U, Bergow C, Hirmer S, Schüler C, Erben RG (2009) Vitamin D independent therapeutic effects of extracellular calcium in a mouse model of adult-onset secondary hyperparathyroidism. J Bone Miner Res 24:22-32. IF 6.00