RAMB Novembro/Dezembro 2015

levated

serum

osteoprotegerin

levels

women

friend

foe

ssoc

ras

2015; 61(6):524-529

525

currently available have stimulated research into the patho-

physiology of osteoporosis and the study of new drugs

for treatment.

It should be noted that several researchers are look-

ing for alternatives to improve or preserve bone mass with

less side effects.

Therefore, there is need for greater un-

derstanding of bone biology to devise new strategies and

therapies to treat osteoporosis.

Knowledge of the molec-

ular mechanisms involved in the bone remodeling pro-

cess is of paramount importance.

The onset of bone resorption is controlled by sever-

al mediators, including the receptor activator of nuclear

factor-kappa B ligand (RANKL), a key cytokine for dif-

ferentiation and activation of osteoclasts and their pre-

cursors. The discovery that bone marrow cells produce a

natural antagonist of RANKL, known as osteoproteger-

in (OPG), led to new lines of therapy. In the beginning,

OPG was used as a treatment to block RANKL, and was

initially successful. However, OPG antibodies seem to ap-

pear after its use, which makes its application as a treat-

ment for osteoporosis difficult. Next, a monoclonal an-

tibody against RANKL (Denosumab) was developed, which

proved to be highly effective in the reduction of bone frac-

tures, and is currently one of the best therapeutic options

for the treatment of osteoporosis.

3,4

New treatments for osteoporosis are, therefore, based

on a better understanding of bone biology and the devel-

opment of new, highly specific compounds, with fewer

side effects. This review aims to evaluate the role of os-

teoprotegerin on bone tissue and other local targets for

better understanding of the physiology of this protein.

ethods

The scientific databases consulted were: PubMed-Med-

line and Cochrane. A manual search from the references

of reviews (narrative or systematic) was also performed.

It included studies available in Portuguese, English, French

or Spanish, whenever full texts were available. We used

keywords (MeSH terms) grouped into the following syn-

taxes: (osteoprotegerin OR osteoclastogenesis inhibitory

factor OR receptors, tumor necrosis factor, member 11b

OR tumor necrosis factor receptor superfamily, member

11b OR FDCR-1 protein OR FDCR 1 protein OR OCIF

protein OR follicular dendritic cell-derived receptor-1)

AND (bones AND bone OR bones AND bone tissue OR

bones OR bone tissue OR cardiovascular diseases). Ex-

perimental studies were included, as well as case reports,

case series, cohort studies and controlled clinical trials

(randomized or otherwise). Studies presenting prelimi-

nary results were excluded from the evaluation.

After submitting the search strategy on the primary

databases, 1,971 articles were retrieved, after which as-

sessment of titles and abstracts resulted in thirty-nine

studies considered for analysis.

steoprotegerin

(OPG)

In 1997, Simonet et al.

described a glycoprotein present

in various organs of mice and rats (bone marrow, stom-

ach, intestines, skin, liver, heart, lung and kidney), a mem-

ber of the TNF receptor superfamily involved in bone

mineral density, and named it osteoprotegerin (OPG),

also known as an osteoclast inhibitory factor that regu-

lates bone resorption. OPG is synthesized as a monomer

(60 kDa), mounted as a homodimer within the cell, and

then released into the blood stream, primarily as a ho-

modimer linked by disulfide bridges.

OPG was identified as a cytokine member of the TNF

receptor superfamily that binds to two ligands, the recep-

tor activator of nuclear factor kappa-B ligand (RANKL),

a key cytokine for the differentiation of osteoclasts, and

a ligand related to the induction of apoptosis (TRAIL),

involved in immune surveillance.

After binding to the

first ligand, OPG inhibits the activation of osteoclasts,

while the binding between OPG and TRAIL prevents apop-

tosis of tumor cells. Thus, as a decoding receiver for

RANKL and TRAIL, OPG inhibits the regulation effects

of nuclear factor kB on inflammation, and on the skele-

tal and vascular systems, preventing apoptosis induced

by TRAIL.

The OPG molecule consists of three structural do-

mains that influence its biological function. The N-ter-

minal portion is a cysteine rich domain important for di-

merization and osteoclastogenesis, while the C-terminal

portion contains death domains and a heparin binding

domain. The latter domain is able to interact with differ-

ent proteoglycans, including heparan sulfate and hepa-

rin.

The connection between OPG and heparan sulfate

present on the cell surface has been described in myelo-

cells and human monocytes.

As mentioned, OPG is expressed highly in many or-

gans, being produced by macrophages, the endothelium

and smooth muscle cells and released into the blood

stream.

OPG is also found in the electron-bodies of

platelets, which is associated with the Von Willebrand

factor.

It has also been observed that TNF-

and IL-1

increase levels of OPG, indicating that activation of en-

dothelial cells by proinflammatory cytokines can be a pos-

sible source of circulating OPG in patients with cardiovas-

cular disease.

In vitro

experiments have shown that after

stimulation with TNF-

, human smooth muscle cells pro-