Osteoprotegerin and Adhesion Molecules - Adhesion Molecules - page 276

Fig. 4 Ef ect of OPG on HUVEC angiopoietin-2 expression assessed by immunohistochemistry.
Images are representative of four independent experiments. Endothelial cells were incubated
with isotype control antibody (negative control) (A), 0 treatment (B) or 10 ng/mL OPG for 10
hr (C). Images were taken at ×10 magnii cation (B and C). Treatment with OPG is associated
with increased immunostaining for angiopoietin-2 demonstrated in a granular pat ern (positive
granules identii ed by arrows), as previously described [18]. Reproduced with permission from
Mangan et al. (2007).
was blocked (Fig. 5) . h ese i ndings suggest angiopoietin-2 is a key regulator
of endothelial cell inl ammatory responses. Ang-2 may control endothelial
responsiveness in dif erent situations. h us, in the presence of low levels of Ang-2
the ability of pro-inl ammatory cytokines to promote leukocyte accumulation is
limited. In contrast, when Ang-2 is expressed at high concentrations, the ef ects of
pro-inl ammatory cytokines are augmented. h e ability of OPG to promote Ang-2
expression is a potentially important mechanism by which this glycoprotein can
promote inl ammation-based pathology.
RANK/RANKL AND ADHESION MOLECULES
Binding of RANKL to its receptor RANK on endothelial cells stimulates
proliferation, migration and activation of endothelial cells, resulting in promotion
of angiogenesis. RANKL also stimulates inl ammatory responses by increasing
endothelial cell-leukocyte interactions and the expression of cell adhesion molecules
ICAM-1 and VCAM-1 on endothelial cells (Min et al. 2005). h ese ef ects occur
through a signalling cascade leading to NF-kB activation. h us, if OPG was solely
a RANK/RANKL inhibitor, then one would expect OPG to attenuate adhesion
molecule expression, which is not the case, as we and others have shown that OPG
augments adhesion molecule expression. h e relative balance of the ef ects of
OPG and RANKL likely vary in vivo depending on the other cytokine milieux and
relative concentrations of the proteins. Since OPG is found within the circulation
at much greater concentrations, however, it is likely its ef ects dominate.