HYPERTONIA ÉS NEPHROLOGIA - eLitMed.hu

16 MARKUS KETTELER HYPERTONIA ÉS NEPHROLOGIA
implicated that elevated phosphate
concentrations may additionally induce
a phenotypic switch of vascular
smooth muscle cells into osteoblastlike
cells. Jono et al. demonstrated in
cultured vascular smooth muscle cells
(VSCM) that an elevation of the phosphate
concentration in the culture medium
from 1.4 to 2.0 mmol/l indeed
caused hydroxyapatite formation, but
that this effect was clearly dependent
on a rise in the intracellular phosphate
concentration (27). Moreover, this
group observed the formation of matrix
vesicles, an upregulation of the
osteoblast transcription factor cbfa-1
and de novo expression of bonerelated
proteins including alkaline
phosphatase, osteopontin and osteocalcin
by VSCM under high phosphate
culture conditions, indicating
an osteogenic dedifferentiation of this
cell type (27). These data, together
with the immunohistochemical detection
of cbfa-1, alkaline phosphatase
and osteopontin in calcified epigastric
arteries by Sharon Moe’s group (28,
29), suggest that hyperphosphatemiadependent
vascular calcification is an
active cellular process in uremic patients.
In view of these observations,
any therapeutic means to decrease
phosphate load and to prevent
hyperphosphatemia in order to suppress
extraosseous calcifications are
certainly of major importance.
Table 1.
CALCIFICATION INHIBITORS
As pointed out above, a highly regulated
balance in the extracellular environment
seems to be necessary to prevent
calcium and phosphate precipitation
in mammals, since the physiological
serum concentrations of these ions
exceed their solubility product in an
aqueous solution and should thus precipitate
immediately. Mostly transgenic
animal experiments have broadened
our understanding of calcification
processes and identified functional
characteristics of calcium-regulatory
factors and their calcification inhibitory
properties. Two of these factors
(matrix Gla Protein, fetuin-A)
and some of their potential clinical implications
will be discussed in the following
paragraphs (table 1).
MATRIX GLA PROTEIN (MGP)
MGP is a 10 kD Gla protein expressed
in chondrocytes and VSMC.
MGP requires activation via vitamin
K-dependent -carboxylation in order
to acting locally as a potent inhibitor
of cartilage and arterial calcification
(30,31). Accordingly, MGP-deficient
(MGP -/- ) mice develop excessive
calcifications cartilage and of the aortic
media that predominantly localize
to the elastic lamellae (31). Aortic
calcifications also include cartilageous
Characteristics of the calcification inhibitors matrix Gla protein and fetuin-A
Matrix Gla Protein
Fetuin-A
Molecular weight 10 kD 62 kD
Cellular source
Phenotype of knockout mice
Properties
VSMC;
Cartilage
lethal (aortic rupture);
arterial medial calcification;
cartilagenous calcification
requires Vitamin-K-dependent
activation to act as a local
precipitation inhibitor
(-carboxylation)
Hepatocytes
systemic soft-tissue and
parenchymatous calcifications
(spontaneously in DBA/2 mice,
following vitamin D treatment in
C57Bl/6 mice)
“soluble” TGF--antagonist;
modulation of insulin receptor
sensitivity
metaplasia within the vessel wall and
are finally lethal at 6-8 weeks of age
due to aortic rupture (“fracture”) and
subsequent internal hemorrhage.
In humans, loss-of-function mutations
of the MGP gene (so-called
Keutel syndrome) lead to a phenotype
clinically characterized by cartilage
and, as observed by autopsies of affected
individuals, vascular medial
calcifications (32). In atherosclerotic
disease, MGP expression was found to
be increased especially in lipid-rich areas
of plaques and seemed to surround
calcifying areas (33). This pattern suggests
that local MGP upregulation
may be an important mechanism
counteracting excessive vascular calcification.
Since MGP requires sufficient
vitamin K availability, genuine
or aquired vitamin K deficiencies predispose
to vascular calcification. In addition,
local deficiency may occur at
heavily calcified sites with high vitamin
K turnover, subsequently leading
to the production of undercarboxylated
inactive MGP and further progression
of the calcification process. In
this way the combination of initial
calcifications and a subclinical vitamin
K-deficiency may strongly amplify the
local synthesis of inactive MGP antigen.
This may be clinically important
when antagonists such as warfarin or
phenprocoumon are used in calcification-prone
patients with renal failure,
however, it currently seems to early to
generate clear-cut clinical advice on
limiting the use of vitamin K-antagonists
in uremic patients based on
these theoretical and experimental
considerations.
FETUIN-A (2-HEREMANS SCHMID
GLYCOPROTEIN, AHSG)
Fetuin-A is a major systemic inhibitor
of calcification accounting
for approximately 50% of the precipitation
inhibitory capacity of serum
(34, 35). Fetuin-A is synthesized
by hepatocytes, occurs in the
extracellular space in high concentrations
(0.5–1.0 g/l) and, importantly,
is regulated as a negative
acute-phase protein (36). In vitro,
fetuin-A has been shown to be a