**5.3 Soluble RAGE generated by shedding**

It has also been suggested that some sRAGE isoforms that could act as decoy receptors may be cleaved proteolytically from the native RAGE expressed on the cell surface 102, suggesting heterogeneity of the origin and nature of sRAGE. This proteolytic generation of sRAGE was initially described as occurring in mice 103. Recent studies suggest that ADAM10 and MMP9 to be involved in RAGE shedding 13, 14. ADAM is known as a shedase to shed several inflammatory receptors and can be involved in regulation of RAGE/sRAGE balance. A RAGE gene polymorphism is shown to be strongly associated with higher sRAGE levels, although the mechanism by which the polymorphism alters the sRAGE levels remains to be elucidated 104. Thus, the molecular heterogeneity of the diverse types of sRAGE in human plasma could exert significant protective effects against RAGE-mediated toxicity. However, the endogenous action of sRAGE may not be confined to a decoy function against RAGE-signaling. In HMGB1-induced arthritis model, for example, sRAGE is found to interact with Mac-1, and act as an important proinflammatory and chemotactic molecule 105. Further analyses are warranted to understand more about the endogenous activity of sRAGE.
