Osteoprotegerin and adhesion molecules

The glycoprotein osteoprotegerin (OPG) plays an important role in controlling normal bone remodelling by inhibiting osteoclast function. More recently, OPG has been implicated in a number of diseases associated with inflammation. This chapter describes current work being undertaken to try and understand the mechanisms underlying the association between high circulating levels of OPG and inflammatory pathologies. Human in vitro work suggests OPG promotes leukocyte adhesion via at least two mechanisms. It stimulates the upregulation of angiopoietin-2 within endothelium, thereby promoting endothelial responsiveness to the pro-inflammatory cytokine tumour necrosis factor alpha. Thus, OPG acts in concert with pro-inflammatory cytokines to promote adhesion molecule upregulation and favour leukocyte recruitment. It also has the ability to cause rapid increases in leukocyte adhesion to the endothelium by acting as a direct bridge between leukocytes and endothelial cells. Despite this convincing data for a pro-inflammatory role of OPG in human cells, in vitro studies in knockout mouse models have not confirmed the role of OPG in inflammation. The reason for this disparity is currently unknown. Further studies using different animal models and alternative ways of studying human disease will be required to clarify these disparities