Published online before print August 23, 2007, doi: 10.1161/ATVBAHA.107.144824
© 2007 American Heart Association, Inc.
Brief Reviews |
Osteopontin
A Multifunctional Molecule Regulating Chronic Inflammation and Vascular Disease
From the Department of Bioengineering (M.S., C.M.G.), University of Washington, Seattle; and the Maine Medical Center Research Institute (L.L.), Scarborough.
Correspondence to Marta Scatena, Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195. E-mail mscatena{at}u.washington.edu
Osteopontin (OPN) is a multifunctional molecule highly expressed in chronic inflammatory and autoimmune diseases, and it is specifically localized in and around inflammatory cells. OPN is a secreted adhesive molecule, and it is thought to aid in the recruitment of monocytes-macrophages and to regulate cytokine production in macrophages, dendritic cells, and T-cells. OPN has been classified as T-helper 1 cytokine and thus believed to exacerbate inflammation in several chronic inflammatory diseases, including atherosclerosis. Besides proinflammatory functions, physiologically OPN is a potent inhibitor of mineralization, it prevents ectopic calcium deposits and is a potent inducible inhibitor of vascular calcification. Clinically, OPN plasma levels have been found associated with various inflammatory diseases, including cardiovascular burden. It is thus imperative to dissect the OPN proinflammatory and anticalcific functions. OPN recruitment functions of inflammatory cells are thought to be mediated through its adhesive domains, especially the arginine-glycine-aspartate (RGD) sequence that interacts with several integrin heterodimers. However, the integrin receptors and intracellular pathways mediating OPN effects on immune cells are not well established. Furthermore, several studies show that OPN is cleaved by at least 2 classes of proteases: thrombin and matrix-metalloproteases (MMPs). Most importantly, at least in vitro, fragments generated by cleavage not only maintain OPN adhesive functions but also expose new active domains that may impart new activities. The role for OPN proteolytic fragments in vivo is almost completely unexplored. We believe that further knowledge of the effects of OPN fragments on cell responses might help in designing therapeutics targeting inflammatory and cardiovascular diseases.
Osteopontin OPN is expressed in chronic inflammatory diseases and regulates chemotaxis and cytokine production. Although OPN adhesive domains are characterized, signaling pathways mediating OPN effects on immune cells are not well established. OPN is cleaved by thrombin and matrix-metalloproteases to generate fragments with novel receptor binding sites and activity, suggesting that proteolysis is an important mechanism to regulate OPN function.
Key Words: osteopontin • osteopontin proteolytic processing • inflammation • atherosclerosis
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