15-01-2013, 12:07 PM
Untangling Klotho’s Role in Calcium Homeostasis
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klotho was identified as a putative
aging gene in 1997 when one of the
mouse strains created in a program
of randominsertional mutagenesis was
found to be short-lived and displayed
atherosclerosis, osteopenia, skin atrophy,
and pulmonary emphysema
(Kuro-o et al., 1997). 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 b-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., 2003). 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., 2006),
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 lowaffinity
to high-affinity FGF23 receptors
(Urakawa et al., 2006; Kurosu
et al., 2006). Imura et al. (2007) now report
that klotho is also a regulator of
calcium homeostasis on its own.
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., 2005), and NaPi2a, the sodiumcoupled
phosphate transporter in the
proximal tubule (personal communication,
M. Kuro-o).