Osteoprotegerin and Adhesion Molecules - Adhesion Molecules - page 270

INTRODUCTION
Osteoprotegerin (OPG) is a soluble glycoprotein originally identii ed to play a
fundamental role in inhibiting osteoclast function and dif erentiation by blocking
the interaction between the ligand receptor activator of NF-кB ligand (RANKL)
and receptor activator of NF-кB (RANK) expressed on osteoclasts (Simonet et al.
1997). In this chapter, we discuss the putative ef ects of OPG outside the recognized
role of OPG in bone remodelling. We initially discuss human association data
linking OPG with human diseases known to involve inl ammation. We then centre
our discussion on recent investigations carried out in our laboratory looking at the
interaction between OPG and leukocyte adhesion molecules.
THE OPG, RANKL AND RANK INTERACTION
No discussion about OPG is possible without mention of its relationship with
RANKL and RANK (Schoppet et al. 2002, Collin-Osdoby 2004). RANKL,
expressed on a variety of cells, such as osteoblasts, stromal and T cells binds
RANK present on other cell types, including osteoclasts, endothelial cells,
monocytes and dendritic cells. h ere are very low concentrations of soluble
RANKL in the circulation of healthy individuals. In contrast, OPG is a soluble
glycoprotein expressed in most human tissues and circulates at ng/ml quantities.
OPG has high ai nity for RANKL and therefore blocks the interaction between
RANKL and RANK, explaining its ability to inhibit osteoclast activation and bone
remodelling (Simonet et al. 1997). OPG also displays ability to bind other ligands,
such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and
thereby block their functions (Emery 1998). It is assumed that many of the ef ects
of OPG are due to binding ligands, thereby blocking their function, although in
the authors' opinion it is likely that some direct functions of OPG also exist. Given
these interactions of OPG we will also include some discussion of the ef ect of
RANKL within this chapter.
OPG AND INFLAMMATION: HUMAN ASSOCIATION
STUDIES
A role for OPG in bone remodelling has been convincingly demonstrated (Kearns
et al. 2008); however, a direct role in other patho-physiological processes has also
been suggested (Schoppet et al. 2002, Collin-Osdoby 2004). It has been suggested
that OPG plays both protective and pathological roles within the vasculature.
Several studies have shown that OPG at physiological concentrations inl uences
endothelial cell and vascular smooth muscle cell (VSMC) survival and prevents
arterial calcii cation (Van Campenhout and Golledge 2008). Other studies have
shown that expression and release of OPG by endothelial cells and VSMCs is