RAMB Novembro/Dezembro 2015

asso

GRS

526

ssoc

ras

2015; 61(6):524-529

duce large amounts of OPG (up to 30 times more than en-

dothelial cells), whereas insulin production decreases.

Osteoprotegerin and bone tissue

In the mid-1990s, it was discovered that signaling via

RANKL/RANK/OPG plays an important role in the reg-

ulation of bone remodeling.

In bone tissue, osteoblasts

and osteocytes produce RANKL, which in turn binds to

their RANK receptor located on the outer surface of the

plasma membrane of osteoclasts and their precursors,

stimulating activity and osteoclast differentiation, as well

as inhibiting apoptosis, increasing survival of these cells.

Furthermore, OPG acts as a RANK competitor by bind-

ing to RANKL and preventing its interaction with RANK,

thus inhibiting the formation and activity of osteoclasts

The central role of OPG in bone remodeling has been

validated by studies on genetically modified mice with an

increase in OPG expression, resulting in mice with osteo-

petrosis, as there is no differentiation of osteoclasts, and

OPG deletion promoting an excessive increase in osteo-

clastogenesis and the subsequent occurrence of severe os-

teoporosis and fractures.

Transgenic female rats engi-

neered to express high OPG continuously for 1 year

showed an increase in bone volume and density of the

vertebrae and decreased bone resorption, with no experi-

enced side effects.

Thus, OPG is considered a natural

antagonist of RANKL and a potent inhibitor of bone re-

sorption, with clear protective ability against bone loss.

Furthermore, several experimental studies have shown

that OPG not only acts as an inhibitor of bone resorp-

tion, but its dysfunction in the RANKL/RANK/OPG path-

way is related to several bone remodeling disorders, such

as osteoporosis, bone loss induced by glucocorticoids,

Paget’s bone disease and bone metastases.

Due to its anti-osteoclastogenesis effect, OPG has

been studied and employed as a treatment for bone loss

and osteoporosis.

It has been shown that the production

of OPG can be stimulated

in vitro

by agents used against

osteoporosis, such as 17

-estradiol,

raloxifene,

bisphos-

phonates

and mechanical stimuli.

In vivo

studies also

demonstrate that parenteral administration of recombi-

nant OPG in healthy rodents results in a marked increase

in bone mass and volume, and a decrease in the number

and activity of osteoclasts, in addition to completely pre-

venting bone loss induced by ovariectomy, although with-

out adverse effects.

In primates, treatment with recom-

binant OPG promotes an increase in bone mineral

density.

Moreover, clinical studies on post-menopaus-

al women have shown that OPG administration can re-

duce bone resorption and the incidence of fractures.

18,21

Despite its beneficial effects against bone loss, a po-

tential concern with the use of OPG is a possible excess

accumulation of newly formed bone tissue, and little re-

sorbed bone tissue because of its strong anti-osteoclas-

togenesis action.

However, in a study in primates, rele-

vant toxicological effects on bone were not found

and,

in human studies, only moderate asymptomatic hypocal-

cemia was observed two to eight days after the dose.

Nevertheless more studies are needed to further investi-

gate the possible side effects of treatment with OPG on

the bone tissue.

Osteoprotegerin and cardiovascular disease

There is evidence toward the involvement of OPG in the

pathogenesis of atherosclerosis and cardiovascular dis-

eases (CVD), amplifying the adverse effects of inflamma-

tion and of various risk factors such as hyperlipidemia,

endothelial dysfunction,

diabetes mellitus

and hyperten-

sion.

24,25

Thus, a series of epidemiological studies have

shown that increased levels of circulating OPG are asso-

ciated with a significant and independent predictive val-

ue of the mortality/morbidity of cardiovascular calcifica-

tion, suggesting that OPG is a possible mediator of

vascular calcification.

Arterial calcification is a part of

the atherosclerotic process leading to clinical cardiovas-

cular disease. The presence of OPG in atherosclerotic

plaques has been described, and studies have shown that

it is located in areas of calcification.

High serum concentrations of OPG were correlated

to the severity of peripheral arterial disease

and heart

failure,

as well as symptomatic carotid stenosis,

unsta-

ble angina,

vulnerable carotid plaques,

acute myocar-

dial infarction and risk of death compared to controls

with stable atherosclerosis.

The relationship between OPG and CVD is support-

ed by studies that show stimulation of OPG polymor-

phism, according to morphology and vascular function.

The clinical relevance of polymorphisms is based on the

fact that serum levels of OPG influence functional activ-

ity. Recently, three polymorphisms of the OPG gene have

been described (T245G, T950C and G1181C), related to

the serum increase of this glycoprotein, which is found

more frequently in patients with atherosclerotic plaques

in the carotid

or in diabetic patients with a history of

ischemic stroke.

Using animal models, Bucay et al.

showed that OPG

knockout mice develop spontaneous arterial calcification;

therefore, OPG appears to protect against vascular calcifi-

cation. Furthermore, in ApoE knockout mice (a well-known

model for atherosclerosis), depletion of OPG increases the