49 / 83
E
levated
serum
osteoprotegerin
levels
in
women
:
friend
or
foe
?
R
ev
A
ssoc
M
ed
B
ras
2015; 61(6):524-529
527
progression of atherosclerosis and calcification.
35
There-
fore, high levels of OPG seem to prevent cardiovascular
events in humans. However, the protective role of OPG
found in the animal model has not been observed in hu-
mans. In fact, the increase in OPG levels has been associ-
ated with the severity of cardiovascular disease.
The first association between OPG and CVD in hu-
mans was published in 2001, by Browner et al.,
36
who re-
ported an association between high OPG plasma levels and
increased cardiovascular mortality in a cohort study of 490
women aged over 65. Therefore, associations between se-
rum levels of OPG and traditional CVD risk factors have
been described, including a positive correlation with smok-
ing, fasting blood glucose, advanced age, diabetes and re-
nal failure.
37
In addition, OPG concentrations are positive-
ly correlated with coronary calcification, vascular stiffness
and the presence of unstable atherosclerotic plaques.
38,39
It has been reported that the increase in serum levels
of OPG in patients with acute myocardial infarction is as-
sociated with decreased microcirculation after revascular-
ization.
40
In a population-based cohort study, increased
OPG serum levels appear to be associated with future risk
of myocardial infarction, ischemic stroke and cardiovas-
cular mortality.
41
In a study of large numbers of patients
with different types of cardiovascular disease, there was re-
ported association between increased serum levels of OPG
and the severity of cardiovascular disease. Additionally, in-
creased levels of OPG were directly associated with the size
of myocardial injury, estimated by magnetic resonance.
42,43
Eren et al.
44
suggest that OPGmay play a role in the patho-
genesis of parity-induced atherosclerosis, as an increased
risk of cardiovascular disease and increased the thickness
of the carotid
intima-media
layers was noted.
It should be mentioned that there is still some con-
troversy, as Bjerre
45
reports that increased levels of OPG
are not directly involved with the extent of myocardial in-
jury. The author also reports that high levels of OPG
would be a biomarker for cardiovascular complications.
The fact that OPG is present in platelets may be the link
between increased levels of OPG and thrombosis. Thus,
OPG levels may simply reflect the extent of CVD.
Although clinical results confirm that OPG is an ac-
tive cytokine in a wide range of diseases (osteoporosis, ar-
thritis, vascular calcification, bone cancer related disease),
OPG plasma levels may be associated with the activity of
these diseases.
46
Osteoprotegerin and other organs
OPG is an essential protein in bone remodeling; howev-
er, additional data show different biological functions.
OPG may promote survival and proliferation, and facil-
itate cell migration by blocking apoptosis related to TNF
(TRAIL), glycosaminoglycans or proteoglycans. A num-
ber of
in vitro
tests, pre-clinical and clinical studies also
provide evidence of the involvement of OPG in the im-
mune system.
6
Studies have shown that OPG has a central role in
immune response and may mediate cell survival. Yun et
al.
47
showed that OPG regulates B-cell maturation, as
mice lacking OPG have a higher population of these cells.
Furthermore, the dendritic cells of these mice have an in-
creased capacity to stimulate T cells.
Indeed, OPG increases leukocyte adhesion to endo-
thelial cells
48
and stimulates the proliferation and migra-
tion of human capillary endothelial cells.
49
This study
suggests that OPG has a central role in immune response
and may mediate cell survival. Another function relates
to the fact that OPG is able to bind to TNF (TRAIL), there-
by blocking apoptosis.
50
Candido
51
reports increased
TRAIL and OPG in the serum of patients with diabetic
nephropathy, and that the pro-inflammatory cytokines
and high glucose levels increase TRAIL, whereas OPG is
neutralized by this action.
C
onclusion
Despite osteoprotegerin being a potent inhibitor of bone
loss, high serum levels of this cytokine are indicative of
calcification-related vascular diseases. A deeper knowl-
edge of the mechanisms involved in the association be-
tween OPG serum levels, bone integrity and cardiovascu-
lar disease can provide important data for future
therapeutic interventions.
R
esumo
Níveis séricos elevados de osteoprotegerina na mulher:
aliado ou inimigo?
Introdução:
a osteoprotegerina (OPG) tem surgido como
uma nova candidata para o tratamento da osteoporose;
no entanto, níveis elevados de OPG têm sido relaciona-
dos à calcificação vascular, um fator de risco independen-
te e bem definido para doença cardiovascular (DCV) e
mortalidade. Assim, a ação da OPG nessas situações tem
sido questionada.
Objetivo:
avaliar a ação da OPG no corpo humano, em
especial no tecido ósseo e nas doenças vasculares.
Métodos:
as bases de informação científica consultadas
foram PubMed-Medline e Cochrane, utilizando-se pala-
vras-chave (MeSH terms) agrupadas nas seguintes sinta-