Monocyte macrophage response to beta(2)-microglobulin modified with advanced glycation end products

We recently found that acidic beta(2)-microglobulin (beta(2)m), a major isoform of beta(2)m in amyloid fibrils of patients with dialysis-related amyloidosis (DRA), contained early Amadori products and advanced glycation end products (AGEs) formed nonenzymatically between sugar and protein. Further analysis revealed that acidic beta(2)m induces monocyte chemotaxis and macrophage secretion of bone-resorbing cytokines, suggesting the involvement of acidic beta(2)m in the pathogenesis of DRA. Acidic beta(2)m, however, is a mixture of heterogeneous molecular adducts due to various types of modification. In the present study, we investigated the modification responsible for the biological activity of acidic beta(2)m toward monocytes/macrophages. The presence of a fair amount of beta(2)m species with deamidation was detected in acidic beta(2)m isolated from urine of non-diabetic long-term hemodialysis patients, but deamidated beta(2)m had no biological activity. In contrast, normal beta(2)m acquired the activity upon incubation with glucose in vitro. Among the glycated beta(2)m, the pigmented and fluorescent beta(2)m that formed after a long incubation period, that is, AGE-modified beta(2)m, exhibited biological activity, whereas beta(2)m modified with Amadori products, major Maillard products in acidic beta(2)m had no such activity. These findings suggest that AGEs, although only a minor constituent of acidic beta(2)m, are responsible for monocyte chemotaxis and macrophage secretion of cytokines, implicating the contribution of AGEs to bone and joint destruction in DRA.