Kuro-o et al.  discovered α-Klotho (Klotho) in transgenic mice in which the transgene cassette had serendipitously disrupted the function of this previously unknown gene. Homozygous Klotho hypomorph mice were characterized by severe growth retardation, reduced life span, vascular and soft tissue calcifications, reduced bone mass and atrophy of various organs . On the basis of the phenotype of Klotho hypomorph mice, Klotho was thought to suppress the ageing process . Klotho is a single pass transmembrane protein with a small intracellular and a large extracellular domain. The extracellular part of the protein consists of the two tandem domains KL1 and KL2, which share homology with family 1 glycosidases . There are three isoforms of the Klotho protein, the full-length transmembrane form, a shed soluble form (sKlotho) produced by cleavage of the extracellular part of the protein through membrane-anchored proteolytic enzymes such as ADAM17 and a truncated soluble form produced by alternative splicing of Klotho mRNA . The truncated Klotho protein isoform lacks the KL2 domain in mice and man [3,4], whereas the shed form consists of KL1 and KL2 but lacks the transmembrane and intracellular parts of the protein.
Klotho is mainly expressed in the kidney in proximal and distal tubules, in the choroid plexus in the brain and in the chief cells of the parathyroid gland [1,5,6]. The kidney is the major source of sKlotho in the blood, because kidney-specific ablation of Klotho leads to profoundly reduced circulating sKlotho levels . Similarly, unilateral nephrectomy in humans reduces circulating sKlotho levels , corroborating the mouse data. Until recently, there has been considerable controversy about the functional role of the different Klotho isoforms. The transmembrane form of Klotho was identified as an obligatory coreceptor for fibroblast growth factor 23 (FGF23) . However, the function of sKlotho has been less clear, and different explanatory models of its putative FGF23-independent mode of action have been proposed, ranging from an enzymatic function as a glycosidase to hormonal functions controlling insulin signalling in insulin target tissues, parathyroid hormone (PTH) secretion in the parathyroid gland or calcium signalling in the heart .
FGF23 belongs to the group of endocrine FGFs, which includes FGF19, FGF21 and FGF23 . FGF23 is a bone-derived hormone mainly produced in osteoblasts and osteocytes. The secretion of FGF23 is stimulated by phosphate, the vitamin D hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D], PTH, iron deficiency and pro-inflammatory cytokines . Only the intact form of the protein is biologically active. The most important physiological functions of FGF23 are in the kidney, wherein it suppresses phosphate reabsorption and synthesis of 1,25(OH)2D in proximal renal tubules [5,12–15], and enhances calcium and sodium reabsorption in distal renal tubules [16,17]. In proximal renal tubules, FGF23 signalling downregulates the membrane expression of the sodium phosphate cotransporters type 2a and 2c (NaPi-2a and 2c) [5,14,15], whereas in distal renal tubules, FGF23 upregulates the apical membrane expression of the epithelial calcium channel transient receptor potential vannilloid-5 (TRPV5) and of the sodium-chloride cotransporter NCC [16,17] (Fig. 1). In bone, FGF23 is a potent suppressor of tissue nonspecific alkaline phosphatase, thereby regulating bone mineralization [18,19]. All paracrine and endocrine FGFs signal through the ubiquitously expressed FGF receptors (FGFRs). There are four different FGFRs, FGFR1, 2, 3 and 4, which are all tyrosine kinase receptors . In addition, tissue-specific splicing leads to ‘b’ and ‘c’ variants of FGFR1, 2 and 3 . Signalling of endocrine FGFs requires the concomitant presence of FGFRs and of the coreceptors α and β-Klotho . The renal actions of FGF23 are Klotho dependent under physiological conditions, with FGFR1c probably being the most important FGFR mediating the hormonal actions of FGF23 [9,21].
A hallmark of Klotho-deficient mouse models is a premature ageing-like phenotype . Klotho-deficient mice are characterized by early death, soft tissue calcifications, organ atrophy, osteomalacia, hypercalcemia, hyperphosphatemia and elevated circulating 1,25(OH)2D [1,22]. Fgf23-deficient mice have an almost identical phenotype [23,24]. It is now firmly established that the severe phenotype in Klotho and Fgf23-deficient mice is caused by unleashed production of 1,25(OH)2D due to ablation of FGF23 signalling in the kidney. In the absence of the suppressive effect of FGF23 signalling on renal 1α–hydroxylase, the normally tight regulation of this enzyme fails, and leads to excessive, unregulated production of 1,25(OH)2D. The subsequent intoxication with 1,25(OH)2D causes hypercalcemia and hyperphosphatemia, which in turn leads to soft tissue calcifications and early lethality. Consequently, ablation of the vitamin D signalling pathway rescues both Klotho and Fgf23-deficient mice [25,26]. Hence, the ageing-like phenotype in Klotho and Fgf23-deficient mice is actually caused by a disturbance of mineral homeostasis.
The purpose of this review is to highlight the recent progress in our understanding of Klotho's role in mineral metabolism. The last year has seen striking advances in this area, which collectively represent a quantum leap in our understanding of Klotho biology.
STRUCTURAL BASIS OF THE FIBROBLAST GROWTH FACTOR RECEPTOR-KLOTHO-FGF23 INTERACTION
Urakawa et al.  had shown that transmembrane αKlotho is an obligatory coreceptor for high affinity binding of the ligand FGF23 to FGFR1c on target cells. Transmembrane Klotho increases the binding affinity of FGFR1c to FGF23 by a factor of nearly 20 [27,28]. However, the complete atomic structure of the ligand-receptor-coreceptor complex was not known. In a recent milestone article, Chen et al. [29▪▪] crystallized the ternary complex consisting of the extracellular domain of FGFR1c, FGF23 and the Klotho ectodomain, and provided the atomic structure of the complex at 3 [Latin Capital Letter A with Ring above and Acute] resolution. In this complex, FGF23 binds in a groove formed between the D2 and D3 domains of FGFR1c, and between the KL1 and KL2 domains of Klotho, respectively. The ternary complex is stabilized by the interaction of Klotho's receptor binding arm with FGFR1c (Fig. 1). Moreover, Chen et al.[29▪▪] showed that two ternary FGFR1c/Klotho/FGF23 complexes dimerize with the help of heparan sulfate to form a 2 : 2:2 : 2 quaternary dimer complex for signal transduction. The elucidation of the 3D atomic structure of the FGFR/Klotho/FGF23 complex is a major achievement, because it significantly improves our understanding of the molecular mechanisms involved in FGF23 signalling. This improved knowledge may form the basis for the future development of small molecule modulators of this signalling pathway.
MODE OF ACTION OF SOLUBLE KLOTHO
During the past two decades, there has been a considerable controversy regarding the role of soluble Klotho in the regulation of mineral metabolism and organ function. It has been proposed that sKlotho may act, in a FGF23-independent manner, as a hormone inhibiting insulin signalling , suppressing PTH secretion in the parathyroid gland , and protecting the myocardium by inhibiting calcium signalling through binding to ganglioside-containing lipid rafts [32,33]. However, all attempts to characterize a specific receptor for sKlotho, apart from FGFRs, have failed . Alternative models of sKlothos's function in mineral metabolism are built on an enzymatic activity of sKlotho as glucuronidase or sialidase [34–37], thereby modulating the function and abundance of membrane glycoproteins by changing their glycosylation patterns.
As mentioned above, the KL1 and KL2 domains of Klotho are homologous to family 1 glycosidases. However, both domains lack one of the two essential active site glutamates, which are highly conserved in this family of glycosidases . Nevertheless, it has been proposed that sKlotho regulates renal calcium, potassium and phosphate handling through Klotho's putative enzymatic activity in a FGF23-independent manner. Chang et al.  and later Cha et al.  reported that Klotho regulates calcium metabolism by changing the glycosylation pattern of the TRPV5 and TRPV6 calcium channels through its putative sialidase activity, thereby increasing the apical membrane abundance and channel activity of TRPV5 and TRPV6 in the distal nephron. A similar mechanism was proposed for the renal outer medullary potassium channel 1 (ROMK1) . Furthermore, Hu et al.  reported that Klotho, through a putative glucuronidase activity, is able to suppress phosphate reabsorption from urine by inhibiting the activity of NaPi2a in renal proximal tubular epithelium.
However, the recent seminal study by Chen et al. [29▪▪] has provided solid experimental evidence that Klotho lacks any biologically relevant glycosidase activity. The work of the latter authors refutes the possibility that sKlotho regulates mineral metabolism through its enzymatic activity. Rather, Chen et al. [29▪▪] showed that soluble and transmembrane Klotho possess similar capacities to facilitate FGF23 signalling in vitro. Furthermore, injection of recombinant sKlotho into wild-type mice resulted in a small, but significant increase in urinary phosphate excretion. Importantly, when the latter authors injected a mutated form of sKlotho lacking the FGF receptor binding arm into normal mice, they found a striking downregulation of FGF23 target genes in the kidney, together with hyperphosphatemia. These findings indicate that the effects of sKlotho on mineral metabolism require interaction with FGFRs. Hence, mutant sKlotho lacking the FGF receptor binding arm acts as a dominant negative coreceptor in vivo, interfering with FGF23 signalling in target tissues. In summary, Chen et al. [29▪▪] have clearly and convincingly shown that sKlotho serves as a soluble coreceptor for canonical FGF23 signalling (Fig. 1).
This notion is supported by additional, independent lines of evidence: Hum et al. [39▪] recently reported that both stable delivery of sKlotho by a viral vector, and acute injection of sKlotho lowered serum phosphate in Klotho-deficient mice. In addition, they observed a profound stimulation of bony FGF23 secretion in Klotho-deficient mice overexpressing sKlotho, an effect that could be explained by the FGFR1-dependent stimulation of osteoblastic FGF23 secretion by FGF23 and sKlotho. Similarly, an earlier study by Shalhoub et al.  also demonstrated that sKlotho enhances the suppressive effect of FGF23 on alkaline phosphatase in mouse osteoblast-like cells in an FGFR1-dependent manner. Collectively, these findings are in full agreement with the notion that sKlotho is an on-demand circulating coreceptor facilitating FGF23 signalling in different tissues (Fig. 1).
Current open questions in this context are: First, what is the relative contribution of transmembrane Klotho vs. sKlotho–mediated FGF23 signalling in target tissues under normal circumstances? Second, is shedding of sKlotho in the kidney regulated? Third, as FGFR1c is expressed almost ubiquitously, does sKlotho enhance FGF23 signalling in a body-wide fashion? In principle, biologically relevant levels of circulating sKlotho should render all target cells expressing FGFR1c FGF23-sensitive. In an attempt to answer the question regarding the relative contribution of transmembrane vs. soluble Klotho for renal FGF23 signalling, we recently cotreated 200 μm thick live kidney slices isolated from wild-type and Klotho-deficient mice ex vivo with sKlotho and FGF23 [41▪▪]. We found that cotreatment with sKlotho did not modulate the FGF23-induced changes in renal tubular calcium, sodium or phosphate transport monitored by 2-photon microscopy in wild-type and Klotho-deficient kidney slices, suggesting that transmembrane Klotho is by far more important than sKlotho for FGF23-mediated signalling in the kidney under near-physiological circumstances [41▪▪]. However, a caveat of the latter model is that the results may be biased by different migration velocities of proteins with grossly different sizes such as sKlotho (130 kDa) and FGF23 (32 kDa) in intact tissues. Therefore, it is unclear whether the latter model is predictive of the in-vivo situation.
Collectively, the abovementioned studies have provided solid evidence that neither transmembrane nor soluble Klotho have FGF23-independent functions. Chen et al. [29▪▪] conclude that ‘In light of these data, we propose that the pleiotropic antiaging effects of α–Klotho are all dependent on FGF23’. A recent study performed in our laboratory fully corroborates this conclusion. To examine the existence of physiologically relevant, FGF23-independent effects of Klotho on mineral homeostasis in vivo, we generated triple knockout mice with simultaneous deficiency in Fgf23 and Klotho and a nonfunctioning vitamin D receptor (VDR) (Fgf23−/−/Klotho−/−/VDR▵/▵, Fgf23/Klotho/VDR). The rationale behind crossing Fgf23 and Klotho-deficient mice with VDR mutant mice is that Fgf23 and Klotho null mice can be studied at older ages only when vitamin D signalling is ablated [25,26]. We found that Fgf23/Klotho/VDR triple knockout mice were phenocopies of Fgf23/VDR double knockout mice, and that Fgf23/Klotho double knockout mice were phenocopies of single Fgf23 knockout mice, independent of age or sex [41▪▪]. These results strongly argue against any physiologically relevant, FGF23-independent effects of Klotho, regardless of its isoform, on mineral homeostasis or ageing. Taken together, there is now overwhelming evidence that the main physiological function of transmembrane and soluble Klotho for mineral homeostasis in vivo is their role as coreceptors mediating FGF23 actions (Fig. 1).
SECRETED FORM OF KLOTHO
The third isoform of Klotho is a truncated form produced by alternative splicing. It was reported that alternative splicing of the Klotho mRNA gives rise to a secreted, truncated Klotho protein isoform in mice and humans [3,4], but not in rats . Murine alternatively spliced Klotho mRNA lacks exons 4 and 5 , whereas a premature stop codon leads to truncation of the Klotho protein in man . Hence, both the murine and the human secreted Klotho protein isoforms consist of KL1 only and lack the KL2 and transmembrane domains. The lack of the transmembrane domain led to the assumption that the alternative mRNA transcripts code for a secreted isoform of Klotho [3,4].
Notably, the paradigm-shifting study by Mencke et al. [43▪▪] reported that the premature stop codon responsible for putative truncation of the Klotho protein in humans primes the alternatively spliced mRNA for degradation. Hence, these recent data suggest that there may be no secreted Klotho protein in man. Whether a secreted Klotho protein isoform exists in mice has never been robustly tested. Moreover, the data provided by Chen et al.[29▪▪] indirectly suggest that even if a secreted Klotho protein exists, it should be functionally inactive. First, neither KL1 nor KL2 possess biologically relevant glycosidase activity. Therefore, secreted Klotho cannot serve as an enzyme. Second, as both tandem domains are required for the interaction between the ligand FGF23 and Klotho [29▪▪], it can be inferred that the isolated KL1 domain is unable to act as a coreceptor. Hence, the recent advances in the field have cast serious doubts on the notion that a secreted form of Klotho serves any biological function.
PATHOPHYSIOLOGICAL ROLE OF KLOTHO IN ACUTE AND CHRONIC RENAL FAILURE
The advances in Klotho biology described above may have major implications for the pathophysiology of renal disease. There is good evidence from clinical and experimental studies that both acute and chronic renal failure are associated with reduced expression of Klotho in the kidney, and with reduced sKlotho levels in the blood [43▪▪,44–47]. In agreement with these data, kidney transplantation in CKD patients results in a rapid rise in circulating sKlotho, and a decline in circulating FGF23 levels [48▪,49▪]. Conversely, treatment of mice with sKlotho improves outcome in acute and chronic renal injury models [50▪▪]. In light of the above-mentioned novel data regarding the role of sKlotho as a facilitator of FGF23 signalling, we propose that the main pathophysiological effect of the decreases in renal Klotho expression and circulating sKlotho in acute and chronic renal failure may be the induction of renal FGF23 resistance. Thus, the protective effects of sKlotho in experimental renal failure models [46,50▪▪] may at least partially be explained by a reduction of renal FGF23 resistance, a subsequent reduction of serum FGF23 levels as shown recently by Hu et al. [50▪▪], and, hence, indirect protection against FGF23-induced renal and cardiovascular damage. In this context, the recent finding by Smith et al. [51▪▪] that FGF23 is a profibrotic factor in the kidney by stimulating injury-primed fibroblasts may help to explain why an FGF23-lowering effect of sKlotho may per se have antifibrotic effects.
Recently, major advances have been made in the field of Klotho's role in mineral metabolism. First, the atomic structure of the FGFR1c/sKlotho/FGF23 complex, together with a structural model of FGF23-induced receptor activation, has been revealed. Second, it has been shown that soluble Klotho is an on-demand coreceptor for FGF23 signalling. Third, it was demonstrated that the main physiological function of Klotho, independent of its isoform, is its function as a coreceptor for FGF23. Fourth, solid evidence has been provided showing that the alternatively spliced Klotho mRNA is degraded and is not translated into a secreted Klotho protein isoform in humans. Collectively, these advances represent a major step in our understanding of Klotho biology and may have important implications for the pathophysiology of acute and chronic renal failure.
Financial support and sponsorship
This work was supported by a grant from the Austrian Science Fund (FWF P24186-B21) to R.G.E.
Conflicts of interest
The author declares no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho
gene leads to a syndrome resembling ageing. Nature 1997; 390:45–51.
2. Xu Y, Sun Z. Molecular basis of Klotho
: from gene to function in aging. Endocr Rev 2015; 36:174–193.
3. Matsumura Y, Aizawa H, Shiraki-Iida T, et al. Identification of the human klotho
gene and its two transcripts encoding membrane and secreted klotho
protein. Biochem Biophys Res Commun 1998; 242:626–630.
4. Shiraki-Iida T, Aizawa H, Matsumura Y, et al. Structure of the mouse klotho
gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 1998; 424:6–10.
5. Andrukhova O, Zeitz U, Goetz R, et al. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone 2012; 51:621–628.
6. Olauson H, Lindberg K, Amin R, et al. Parathyroid-specific deletion of Klotho
unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 2013; 9:e1003975.
7. Lindberg K, Amin R, Moe OW, et al. The kidney is the principal organ mediating klotho
effects. J Am Soc Nephrol 2014; 25:2169–2175.
8. Kakareko K, Rydzewska-Rosolowska A, Brzosko S, et al. The effect of nephrectomy on Klotho
, FGF-23 and bone metabolism. Int Urol Nephrol 2017; 49:681–688.
9. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho
converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770–774.
10. Itoh N, Ohta H, Konishi M. Endocrine FGFs: evolution, physiology, pathophysiology, and pharmacotherapy. Front Endocrinol (Lausanne) 2015; 6:154.
11. Erben RG. Pleiotropic actions of FGF23. Toxicol Pathol 2017; 45:904–910.
12. Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001; 98:6500–6505.
13. Shimada T, Yamazaki Y, Takahashi M, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 2005; 289:F1088–F1095.
14. Baum M, Schiavi S, Dwarakanath V, et al. Effect of fibroblast growth factor-23
on phosphate transport in proximal tubules. Kidney Int 2005; 68:1148–1153.
15. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19:429–435.
16. Andrukhova O, Smorodchenko A, Egerbacher M, et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J 2014; 33:229–246.
17. Andrukhova O, Slavic S, Smorodchenko A, et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 2014; 6:744–759.
18. Murali SK, Roschger P, Zeitz U, et al. FGF23 regulates bone mineralization in a 1,25(OH) D and Klotho
-independent manner. J Bone Miner Res 2016; 31:129–142.
19. Murali SK, Andrukhova O, Clinkenbeard EL, et al. Excessive osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in Hyp mice. PLoS Biol 2016; 14:e1002427.
20. Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 2015; 4:215–266.
21. Han X, Yang J, Li L, et al. Conditional deletion of Fgfr1 in the proximal and distal tubule identifies distinct roles in phosphate and calcium transport. PLoS One 2016; 11:e0147845.
22. Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho
mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology 2002; 143:683–689.
23. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113:561–568.
24. Sitara D, Razzaque MS, Hesse M, et al. Homozygous ablation of fibroblast growth factor-23
results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 2004; 23:421–432.
25. Hesse M, Frohlich LF, Zeitz U, et al. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol 2007; 26:75–84.
26. Anour R, Andrukhova O, Ritter E, et al. Klotho
lacks a vitamin D independent physiological role in glucose homeostasis, bone turnover, and steady-state PTH secretion in vivo. PLoS One 2012; 7:e31376.
27. Goetz R, Ohnishi M, Kir S, et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J Biol Chem 2012; 287:29134–29146.
28. Goetz R, Ohnishi M, Ding X, et al. Klotho
coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol Cell Biol 2012; 32:1944–1954.
29▪▪. Chen G, Liu Y, Goetz R, et al. alpha-Klotho
is a nonenzymatic molecular scaffold for FGF23 hormone signalling. Nature 2018; 553:461–466.
A landmark study presenting the atomic structure of the ternary FGFR1c/Klotho/FGF23 complex, and showing that soluble Klotho is a bona fide coreceptor for FGF23 signalling, lacking glycosidase activity.
30. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho
. Science 2005; 309:1829–1833.
31. Imura A, Tsuji Y, Murata M, et al. alpha-Klotho
as a regulator of calcium homeostasis. Science 2007; 316:1615–1618.
32. Xie J, Cha SK, An SW, et al. Cardioprotection by Klotho
through downregulation of TRPC6 channels in the mouse heart. Nat Commun 2012; 3:1238.
33. Dalton G, An SW, Al-Juboori SI, et al. Soluble klotho
binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proc Natl Acad Sci U S A 2017; 114:752–757.
34. Tohyama O, Imura A, Iwano A, et al. Klotho
is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 2004; 279:9777–9784.
35. Chang Q, Hoefs S, Van Der Kemp AW, et al. The beta-glucuronidase klotho
hydrolyzes and activates the TRPV5 channel. Science 2005; 310:490–493.
36. Hu MC, Shi M, Zhang J, et al. Klotho
: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010; 24:3438–3450.
37. Cha SK, Ortega B, Kurosu H, et al. Removal of sialic acid involving Klotho
causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 2008; 105:9805–9810.
38. Cha SK, Hu MC, Kurosu H, et al. Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho
. Mol Pharmacol 2009; 76:38–46.
39▪. Hum JM, O’Bryan LM, Tatiparthi AK, et al. Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble Klotho
. J Am Soc Nephrol 2017; 28:1162–1174.
An interesting study providing in-vivo evidence that soluble Klotho faciliates FGF23 signalling.
40. Shalhoub V, Ward SC, Sun B, et al. Fibroblast growth factor 23 (FGF23) and alpha-klotho
stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization. Calcif Tissue Int 2011; 89:140–150.
41▪▪. Andrukhova O, Bayer J, Schuler C, et al. Klotho
lacks a FGF23 independent role in mineral homeostasis
. J Bone Miner Res 2017; 32:2049–2061.
This study provides in-vivo evidence that Klotho, regardless of the isoform, does not have physiologically relevant, FGF23-independent effects on mineral homeostasis.
42. Ohyama Y, Kurabayashi M, Masuda H, et al. Molecular cloning of rat klotho
cDNA: markedly decreased expression of klotho
by acute inflammatory stress. Biochem Biophys Res Commun 1998; 251:920–925.
43▪▪. Mencke R, Harms G, Moser J, et al. Human alternative Klotho
mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease. JCI Insight 2017; 2:pii: 94375.
This study shows that alternatively spliced Klotho mRNA is degraded and not translated into secreted Klotho protein in man.
44. Tan SJ, Smith ER, Holt SG, et al. Soluble klotho
may be a marker of phosphate reabsorption. Clin Kidney J 2017; 10:397–404.
45. Nordholm A, Mace ML, Gravesen E, et al. Klotho
& Activin A in kidney injury Plasma Klotho
is maintained in unilateral obstruction despite no upregulation of Klotho
biosynthesis in contralateral kidney. Am J Physiol Renal Physiol 2017; [Epub ahead of print].
46. Lin W, Li Y, Chen F, et al. Klotho
preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice. Sci Rep 2017; 7:46195.
47. Munoz-Castaneda JR, Herencia C, Pendon-Ruiz de Mier MV, et al. Differential regulation of renal Klotho
and FGFR1 in normal and uremic rats. FASEB J 2017; 31:3858–3867.
48▪. Tan SJ, Crosthwaite A, Langsford D, et al. Mineral adaptations following kidney transplantation. Transpl Int 2017; 30:463–473.
A prospective study showing that soluble Klotho is upregulated, whereas circulating FGF23 is downregulated after kidney transplantation.
49▪. Tranaeus LY, Olauson H, Vavilis G, et al. The FGF23-Klotho
axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease-a prospective cohort study. Pediatr Nephrol 2018; 33:147–157.
A prospective study in paediatric CKD patients showing that soluble Klotho is upregulated, whereas circulating FGF23 is downregulated after kidney transplantation.
50▪▪. Hu MC, Shi M, Gillings N, et al. Recombinant alpha-Klotho
may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 2017; 91:1104–1114.
An interesting study showing that treatment with soluble Klotho improves outcome in murine acute and chronic renal failure models.
51▪▪. Smith ER, Tan SJ, Holt SG, et al. FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts. Sci Rep 2017; 7:3345.
This study suggests that FGF23 is a pro-fibrotic factor in the kidney by activating injury-primed fibroblasts.