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• W2011704851 abstract "klotho was first described as an aging gene and was later shown to be a regulator of phosphate and vitamin D metabolism, acting as a coreceptor for FGF23. Imura et al., 2007Imura A. Tsuji Y. Murata M. Maeda R. Kubota K. Iwano A. Obuse C. Togashi K. Tominaga M. Kita N. et al.Science. 2007; 316: 1615-1618Crossref PubMed Scopus (319) Google Scholar now report that klotho also regulates calcium homeostasis. klotho was first described as an aging gene and was later shown to be a regulator of phosphate and vitamin D metabolism, acting as a coreceptor for FGF23. Imura et al., 2007Imura A. Tsuji Y. Murata M. Maeda R. Kubota K. Iwano A. Obuse C. Togashi K. Tominaga M. Kita N. et al.Science. 2007; 316: 1615-1618Crossref PubMed Scopus (319) Google Scholar now report that klotho also regulates calcium homeostasis. klotho was identified as a putative aging gene in 1997 when one of the mouse strains created in a program of random insertional mutagenesis was found to be short-lived and displayed atherosclerosis, osteopenia, skin atrophy, and pulmonary emphysema (Kuro-o et al., 1997Kuro-o M. Matsumura Y. Aizawa H. Kawaguchi H. Suga T. Utsugi T. Ohyama Y. Kurabayashi M. Kaname T. Kume E. et al.Nature. 1997; 390: 45-51Crossref PubMed Scopus (2488) Google Scholar). Since these traits were viewed as evidence of premature aging, the mutation was named klotho after the spinner of the thread of life, one of the three Fates. The klotho gene encodes a cell-surface protein with a short cytoplasmic tail whose extracellular domain consists of tandem duplicated copies of a β-glucosidase-like sequence, which can be released as a soluble form of Klotho. It was subsequently found that klotho mutant mice had markedly increased levels of calcium, phosphate, and the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (Tsujikawa et al., 2003Tsujikawa H. Kurotaki Y. Fujimori T. Fukuda K. Nabeshima Y. Mol. Endocrinol. 2003; 17: 2393-2403Crossref PubMed Scopus (393) Google Scholar). These animals die prematurely because their kidneys and other tissues become calcified. This, and the somatic features of the klotho phenotype, was reminiscent of mice lacking the FGF23 gene (Urakawa et al., 2006Urakawa I. Yamazaki Y. Shimada T. Iijima K. Hasegawa H. Okawa K. Fujita T. Fukumoto S. Yamashita T. Nature. 2006; 444: 770-774Crossref PubMed Scopus (1302) Google Scholar), which led to the observation that serum levels of FGF23 were markedly elevated in klotho mutant mice, thus establishing that klotho is genetically downstream of FGF23. Further experiments showed that binding to Klotho converts FGF receptors from low-affinity to high-affinity FGF23 receptors (Urakawa et al., 2006Urakawa I. Yamazaki Y. Shimada T. Iijima K. Hasegawa H. Okawa K. Fujita T. Fukumoto S. Yamashita T. Nature. 2006; 444: 770-774Crossref PubMed Scopus (1302) Google Scholar, Kurosu et al., 2006Kurosu H. Ogawa Y. Miyoshi M. Yamamoto M. Nandi A. Rosenblatt K.P. Baum M.G. Schiavi S. Hu M.C. Moe O.W. Kuro-o M. J. Biol. Chem. 2006; 281: 6120-6123Crossref PubMed Scopus (973) Google Scholar). Imura et al., 2007Imura A. Tsuji Y. Murata M. Maeda R. Kubota K. Iwano A. Obuse C. Togashi K. Tominaga M. Kita N. et al.Science. 2007; 316: 1615-1618Crossref PubMed Scopus (319) Google Scholar now report that klotho is also a regulator of calcium homeostasis on its own. Most of the features that resemble premature aging in klotho mutant mice are consequences of 1,25-dihydroxyvitamin D excess. The life span of klotho mutant mice can be increased by a vitamin D-deficient diet (Tsujikawa et al., 2003Tsujikawa H. Kurotaki Y. Fujimori T. Fukuda K. Nabeshima Y. Mol. Endocrinol. 2003; 17: 2393-2403Crossref PubMed Scopus (393) Google Scholar). Removing the synthetic enzyme for 1,25-dihydroxyvitamin D from FGF23−/− mice abolishes all the notable features of the corresponding phenotype, which are probably forms of tissue damage resulting from chronically high calcium and phosphate levels (Sitara et al., 2006Sitara D. Razzaque M.S. St Arnaud R. Huang W. Taguchi T. Erben R.G. Lanske B. Am. J. Pathol. 2006; 169: 2161-2170Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). The pathway by which klotho regulates phosphate and vitamin D metabolism thus intersects with the newly discovered FGF23 pathway. FGF23 is a secreted phosphatonin, a factor that induces renal phosphate wasting and inhibits synthesis of 1,25-dihydroxyvitamin D (White et al., 2006White K.E. Larsson T.E. Econs M.J. Endocr. Rev. 2006; 27: 221-241Crossref PubMed Scopus (128) Google Scholar). FGF23 causes renal phosphate wasting in both inherited and acquired forms of hypophosphatemic rickets. The predominant source of FGF23 is osteocytes and osteoblasts in bone, where its secretion is repressed by dentin matrix protein 1 (DMP1) (Liu et al., 2006Liu S. Zhou J. Tang W. Jiang X. Rowe D.W. Quarles L.D. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E38-E49Crossref PubMed Scopus (366) Google Scholar, Feng et al., 2006Feng J.Q. Ward L.M. Liu S. Lu Y. Xie Y. Yuan B. Yu X. Rauch F. Davis S.I. Zhang S. et al.Nat. Genet. 2006; 38: 1310-1315Crossref PubMed Scopus (861) Google Scholar, Lorenz-Depiereux et al., 2006Lorenz-Depiereux B. Bastepe M. Benet-Pages A. Amyere M. Wagenstaller J. Muller-Barth U. Badenhoop K. Kaiser S.M. Rittmaster R.S. Shlossberg A.H. et al.Nat. Genet. 2006; 38: 1248-1250Crossref PubMed Scopus (408) Google Scholar). The secretion of FGF23 is increased by hyperphosphatemia and 1,25-dihydroxyvitamin D, but the details of its feedback mechanisms and its physiological role remain obscure. klotho is expressed in only three tissues, the distal tubule of the kidney, parathyroid glands, and choroid plexus; however, its function in these tissues is not known. Imura et al., 2007Imura A. Tsuji Y. Murata M. Maeda R. Kubota K. Iwano A. Obuse C. Togashi K. Tominaga M. Kita N. et al.Science. 2007; 316: 1615-1618Crossref PubMed Scopus (319) Google Scholar report that Klotho interacts physically with Na+/K+ ATPase in all three of these tissues. In the choroid plexus, Klotho binds to Na+/K+ ATPase in an intracellular compartment and a fraction of Na+/K+ ATPase appears to traffic to the cell surface with Klotho. [3H]ouabain binding to Na+/K+ ATPase and 86Rb uptake, a measure of Na+/K+ ATPase activity, are decreased, albeit slightly, in klotho−/− mice. The molecular mechanism for this effect of klotho, however, remains to be identified. Imura et al. show that Klotho regulates some aspects of calcium homeostasis. Calcium transport by the choroid plexus is known to be regulated by serum calcium concentration ([Ca2+]); the authors show that cerebrospinal fluid [Ca2+] is lower in klotho−/− mice than in klotho+/+ mice, which have equivalent serum [Ca2+]. [3H]ouabain binding and 86Rb uptake are regulated by medium [Ca2+] in isolated choroid plexus from klotho+/+, but not klotho−/−, mice. The authors infer that calcium- and klotho-dependent recruitment of Na+/K+ ATPase may be involved in the regulation of transepithelial calcium transport by the choroid plexus. The parathyroid glands secrete parathyroid hormone (PTH) to protect against hypocalcemia; secretion of PTH is regulated by a G protein-coupled calcium-sensing receptor (Hofer and Brown, 2003Hofer A.M. Brown E.M. Nat. Rev. Mol. Cell Biol. 2003; 4: 530-538Crossref PubMed Scopus (478) Google Scholar). Imura et al., 2007Imura A. Tsuji Y. Murata M. Maeda R. Kubota K. Iwano A. Obuse C. Togashi K. Tominaga M. Kita N. et al.Science. 2007; 316: 1615-1618Crossref PubMed Scopus (319) Google Scholar show that the secretion of PTH in response to hypocalcemia is blunted in klotho−/− mice. Moreover, secretion of PTH by isolated parathyroid glands in low [Ca2+] medium is decreased equivalently in glands from klotho−/− mice and in ouabain-treated glands from klotho+/+ mice, while treatment of klotho−/− glands with ouabain has no additional effect. These data are consistent with the possibility that klotho regulates PTH secretion through effects on Na+/K+ ATPase. However, the present work does not establish whether the action (or actions) of klotho on Na+/K+ ATPase are central to the effects of klotho on calcium homeostasis. Moreover, because increased production of 1,25-dihydroxyvitamin D in klotho−/− mice causes an increase in serum calcium with suppression of PTH, it isn't clear whether PTH secretory dynamics are altered in vivo as they are in isolated parathyroids. Imura et al. make another important observation—that there is a marked increase in release of Klotho protein from choroid plexus, parathyroid, or kidney incubated in low-[Ca2+] medium. It was previously known that Klotho circulates after release from the cell surface, but this is the first report that the process is regulated. Two renal transporters essential to calcium and phosphate homeostasis have recently been shown to be regulated by extracellular Klotho: TRPV5, the PTH- and vitamin D-responsive calcium transporter in the distal nephron (Chang et al., 2005Chang Q. Hoefs S. van der Kemp A.W. Topala C.N. Bindels R.J. Hoenderop J.G. Science. 2005; 310: 490-493Crossref PubMed Scopus (477) Google Scholar), and NaPi2a, the sodium-coupled phosphate transporter in the proximal tubule (personal communication, M. Kuro-o). In both cases, evidence points to cleavage of glycosyl moieties on the transporter by the β-glucuronidase activity of Klotho as the mechanism by which Klotho regulates surface display; however, this mechanism does not seem to be operational in the case of Klotho regulation of Na+/K+ ATPase. How do the observations of Imura et al., 2007Imura A. Tsuji Y. Murata M. Maeda R. Kubota K. Iwano A. Obuse C. Togashi K. Tominaga M. Kita N. et al.Science. 2007; 316: 1615-1618Crossref PubMed Scopus (319) Google Scholar fit into the physiology of calcium homeostasis? The previous observation that the phenotypes of FGF23−/− and klotho−/− mice are nearly identical (Urakawa et al., 2006Urakawa I. Yamazaki Y. Shimada T. Iijima K. Hasegawa H. Okawa K. Fujita T. Fukumoto S. Yamashita T. Nature. 2006; 444: 770-774Crossref PubMed Scopus (1302) Google Scholar) indicates that many features of Klotho deficiency result from defective FGF23 action. One possibility is that Klotho, in addition to being the coreceptor for FGF23, has other downstream roles. The primary site of FGF23 action in the kidney is predicted to be the distal renal tubule, based on the precise localization of Klotho protein to that nephron segment, but the cells responsible for phosphate reabsorption and vitamin D activation are in the proximal tubule. Could Klotho be released at the site of FGF23 action and serve as an extracellular second messenger to inhibit phosphate reabsorption? Although the present results are tantalizing, it is not yet definite that Klotho plays an appreciable role in calcium homeostasis that is independent of FGF23. Current thoughts regarding the role of FGF23 and Klotho in calcium/vitamin D and bone metabolism are summarized in Figure 1. They predict a circuitous route following the thread of life through the byways of mineral ion metabolism." @default.
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• W2011704851 date "2007-08-01" @default.
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• W2011704851 title "Untangling Klotho's Role in Calcium Homeostasis" @default.
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