Interaction between β2-microglobulin and advanced glycation end products in the development of dialysis related-amyloidosis

Dialysis related amyloidosis (DRA) is a progressive debilitating complication of long-term dialysis. β2-microglobulin (β2m) amyloid deposition occurs preferentially in older patients and initially is located in collagen-rich osteo-articular tissues. Since an age-dependent increase in the formation of advanced glycation end products (AGE) has been observed in collagen-containing structures, we hypothesized that AGE-modified β2m in the amyloid of DRA may be formed locally in osteo-articular structures as a subsequent event of its binding to collagen-AGE. Based on this hypothesis, we investigated the binding between β2m and AGE modified collagen (collagen- AGE) in vitro. Significantly larger amounts of human β2m were bound to types I to IV of immobilized collagen-AGE than to unmodified collagens (P < 0.0001). The quantity of β2m bound to collagen-AGE was dependent on the concentrations of both β2m and of AGE contained in collagen (P < 0.01). Unmodified β2m was more avidly bound to collagen-AGE or collagen in comparison to AGE-modified β2m (P < 0.0001). β2m bound to collagen-AGE could be modified further by nonenzymatic glycosylation during three weeks of incubation with physiologic concentrations of glucose. Similar processes in vivo may be important in the pathobiology of DRA.