Biomedical Engineering Reference
In-Depth Information
It was isolated as a secreted glycoprotein that blocked osteoclast differentiation
from precursor cells, prevented osteoporosis (decreased bone mass) when admin-
istered to ovariectomized rats, and resulted in osteopetrosis (increased bone mass)
when overexpressed in transgenic mice. It was shown that OPG inhibits the differ-
entiation of osteoclast precursors into osteoclasts and also regulates the resorption
of osteoclasts
in vitro
and
in vivo
.
Studies in mutant mice have validated the idea that OPG is identical to the
osteoblast-derived osteoclast inhibitory factor. Transgenic mice overexpressing
OPG exhibit increased bone density and increased mineralization due to a decrease
in osteoclasts terminal differentiation.
OPG is a member of the TNF receptor superfamily. OPG is a protein that
plays a central role in regulating bone mass: it is a cytokine, which can inhibit the
production of osteoclasts. OPG is also known as osteoclastogenesis inhibitory factor
(OCIF). It is a basic glycoprotein comprising 401 amino-acid residues arranged into
seven structural domains, cf. Figure 1.25. It is found as either a 60 kDa monomer
or a 120 kDa dimer linked by disulfide bonds.
Studies have shown that OPG inhibits osteoclastogenesis by binding ODF
(RANKL/OPGL/TRANCE) and blocking its interaction with its receptor, RANK, on
osteoclasts (TRANCE receptor or TRANCE-R).
OPG contains a cysteine-rich amino-terminal domain, a putative death domain,
and a COOH-terminal heparin-binding domain, but unlike other members of the
TNF receptor family, it does not contain a transmembrane domain (Figure 1.25).
Therefore, it is thought to act as a soluble receptor. OPG has been detected in
the bone, heart, lung, liver, stomach, placenta, calvaria, dendritic cells, and blood
vessels [175].
In addition, a role for OPG in the development of germinal centers in secondary
lymphoid tissues has been postulated. OPG has also been implicated as a cell
survival factor: OPG protects endothelial cells from apoptosis induced by serum
withdrawal and NF-
κ
B inactivation.
1.3.5.2
RANK/RANKL
RANKL is produced by a variety of cell types and its expression is regulated by
many physiologic and pathologic factors. Preclinical studies in mice and studies of
human tissues have revealed the functions of RANKL/RANK signaling in normal
1234 5 6 7
H
2
N
COOH
OH
A
B
C
D
Figure 1.25
Schematic structure of osteoprotegerin
OPG polypeptide: A, signaling peptide; B, cysteine-rich
amino-terminal domains; C, putative death domains; and
D, COOH-terminal heparin-binding domain. After [174].
