Klotho and fibroblast growth factor 23 in cerebrospinal fluid in children

Abstract

The fibroblast growth factor (FGF) 23/Klotho axis is a principal regulator of phosphate hemostasis and vitamin D metabolism, but limited data is available on its role in the central nervous system. Here, we investigate soluble α-Klotho (sKlotho) and C-terminal as well as intact FGF23 in cerebrospinal fluid (CSF) and plasma and their relationship to mineral metabolism parameters in humans. In 39 children aged 0.3-16.8 years undergoing lumbar puncture for the exclusion of inflammatory neurological disease, sKlotho and FGF23 were investigated by Western blot analysis, followed by ELISA quantification in CSF and plasma. The percentage of intrathecal synthesis of both proteins was calculated by measuring both the expected and observed CSF/plasma ratios of sKlotho and FGF23. The secreted (KL1) and cleaved (KL1+KL2) isoforms of sKlotho, and FGF23 were clearly detected in CSF in all subjects, although protein levels were lower compared to those of plasma samples (each p < 0.01). The intrathecal percentage of CSF sKlotho and FGF23 synthesis amounted to 98 and 99 %, respectively. CSF sKlotho levels were higher in boys than in girls (p < 0.01), and correlated positively with plasma C-terminal FGF23 concentrations (p < 0.05) and standardized height (p < 0.01). Importantly, there were no significant correlations between plasma and CSF levels of sKlotho or FGF23. Plasma sKlotho as well as C-terminal and intact FGF23, respectively, were associated with parameters of mineral metabolism These results provide evidence that cleaved and secreted sKlotho and FGF23 are present in CSF, mainly derived from brain and affected by sex, height, and mineral metabolism parameters in children. Nevertheless, the absence of significant associations between plasma and CSF levels of Klotho and FGF23, respectively, suggest that the regulation of Klotho and FGF23 may be different between organs secreting these hormones into blood and CSF.

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

“…Since neurons are bathed cerebrospinal fluid that contains shed KL (Imura et al 2004; Yamazaki et al 2010; Semba et al 2014; Kunert et al 2016; Shardell et al 2016), these data suggest that non-cell autonomous action of shed KL affects early progenitors. Although not taking into account quiescent cells or possible NSP fusion events (Reynolds and Rietze 2005), primary NSPs estimate the in vivo potential of cells to exhibit stem cell traits (Pastrana et al 2011).…”

FGF23 Actions on Target Tissues—With and Without Klotho

“…sKL cleavage can also be mediated by the β-APP cleaving enzyme 1 (BACE1), which belongs to the family of β-secretases, and the remaining membrane-associated klotho fragment is further processed and removed by the γ-secretase complex ( 71 , 73 ). The kidney is the major source for sKL ( 73 – 75 ), but also ependymal cells of the choroid plexus in the brain might release sKL by shedding ( 76 – 78 ), and sKL can be detected in the blood ( 73 , 79 – 84 ) and the cerebrospinal fluid (CSF) ( 83 , 84 ). The half-life of sKL in rats is about 7 h ( 73 ), which might be shortened in CKD, where degradation of circulating sKL appears to be increased ( 79 ).…”

Klotho, the Key to Healthy Brain Aging?

“…Secreted KL transcripts are reportedly expressed by the same organs that generate transmembrane KL [ 14 ], but in mice, only the brain is reported to make secreted KL protein [ 29 ]. Although most of our data about human KL function focuses on the transmembrane protein and its important renal role in ion homeostasis, secreted KL was originally described to be the predominant human RNA transcript [ 14 ] and is the major human serum protein form [ 30 ]. Yet to date, secreted KL has no known function.…”