Osteopontin: a protective mediator of cardiac fibrosis?

Osteopontin (OP) is a multifunctional cytokine and adhesion protein that contains an RGD (argininglycin-aspartate) binding sequence that enables it to interact with several integrins, CD44 variants, and other adhesion receptors. OP receptor binding then directly or indirectly activates intracellular signaling pathways, mediating its effects on cell–matrix and cell–cell interactions. OP is increased in response to pro-inflammatory cytokines and mechanical strain in various cell types,1 and the function of its secreted protein can be altered by proteases, including thrombin.2 Thus, OP can exists as an immobilized matrix molecule (eg, in bone, atherosclerotic plaques, or calcified heart valves) or as soluble cytokine. Cell signaling by OP is predominantly mediated through integrin engagement. Cleavage of OP by thrombin exposes integrin binding sites2 (eg, for 9 1), which are important for OP-mediated adhesion/migration. OP is chemotactic for various cell types, most notably monocytes/macrophages, which are attracted to sites of injury and inflammation. The bestcharacterized OP-induced signal pathway is the integrinstimulated FAK-Src-Rho pathway in osteoclasts.1 However, identification and dissection of signal transduction pathways are complicated by the fact that OP potentially binds to several cell surface receptors.