Biomedical Engineering Reference
In-Depth Information
markedly upregulated in response to pro-inl ammatory cytokines like tumour
necrosis factor alpha (TNF-α) and correlates with increased cardiovascular risk
(Van Campenhout and Golledge 2009). A number of the diseases linked with OPG
involve inl ammation as critical in their pathology. Circulating concentrations of
OPG have been associated with the severity of vascular calcii cation, progression
of abdominal aortic aneurysm, complications of atherosclerosis, rheumatoid
arthritis progression and Crohn's disease (Golledge
et al.
2004, Kiechl
et al.
2004,
Bernstein
et al.
2005, Moran
et al.
2005, Clancy
et al.
2006, Geusens
et al.
2006,
Kadoglou
et al.
2008). Whether OPG and/or RANKL are directly involved in
these diseases or their elevated expression is simply a secondary consequence
of the diseases is currently controversial (Van Campenhout and Golledge 2009).
Expression of OPG within tissue from patients with these diseases has also been
related to localized or systemic inl ammation in some but not all studies (Smith
et al.
2003, Golledge
et al.
2004, Gannage-Yared
et al.
2008, Vandooren
et al.
2008).
In this chapter, we discuss evidence for a direct role of OPG in leukocyte adhesion
and hence the inl ammation process.
OPG AND LEUKOCYTE ADHESION
Studies have suggested that OPG promotes leukocyte adhesion, although the
mechanisms involved are currently controversial (Mangan
et al.
2007, Zauli
et al.
2007). Zauli
et al.
(2007) found that incubating cultured human umbilical
vein endothelial cells (HUVECs) and human microvascular endothelial cells
(HMVECs) with recombinant OPG for 16 hr promoted the adhesion of primary
polymorphonuclear neutrophils (PMNs; drawn from healthy volunteers) and
the cell line HL-60 to endothelial cells. Adhesion of leukocytes was maximally
stimulated at concentrations between 0.1 and 0.5 ng/mL, which are similar to levels
reported in the sera
of patients af ected by a number of diseases associated with
inl ammation, such as rheumatoid arthritis (Geusens
et al.
2006), symptomatic
atherosclerosis (Golledge
et al.
2004, Van Campenhout and Golledge 2009) and
abdominal aortic aneurysm (Moran
et al.
2005).
Zauli and colleagues found that
incubating endothelial cells with OPG alone had no ef ect on adhesion molecule
expression. h ese investigators also reported that in the presence of the pro-
inl ammatory cytokine TNF-α, OPG (0.5 ng/ml) did not promote additional
leukocyte adhesion (Zauli
et al.
2007). Further experiments by Zauli
et al.
suggested
that incubation periods as short as 5 min were enough to stimulate increased
adhesion of leukocytes to endothelial cells. Furthermore, the ef ects of OPG could
be stimulated by incubation with either the PMNs or the endothelial cells. Further
experiments provided additional data suggesting that OPG bound to PMNs via
its ligand- (RANKL and TRAIL) binding domain, while endothelial cells bound
to OPG via its heparin-binding domain (Zauli
et al.
2007). h is would suggest
that circulating OPG acts as a bridge between the PMNs and endothelial cells,
facilitating leukocyte rolling and i rm adhesion. h e investigators also reported
