Involvement of β₂-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-α and interleukin-1

β₂-Microglobulin (β₂M) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a complication of long-term hemodialysis. However, the pathological role of β₂M in HAA remains to be determined. Recently, we demonstrated that β₂M in the amyloid deposits of HAA is modified with advanced glycation end products (AGEs) of the Maillard reaction. Since AGEs have been implicated in tissue damage associated with diabetic complications and aging, we investigated the possible involvement of AGE-modified β₂M (AGE-β₂M) in the pathogenesis of HAA. AGE- and normal- β₂M were purified from urine of long-term hemodialysis patients. AGE-β₂M enhanced directed migration (chemotaxis) and random cell migration (chemokinesis) of human monocytes in a dose-dependent manner. However, normal-β₂M did not enhance any migratory activity. AGE-β₂M, but not normal-β₂M, increased the secretion of TNF-α and IL-1β from macrophages. Similar effects were also induced by in vitro prepared AGE-β₂M (normal- β₂M incubated with glucose in vitro for 30 d). When TNF-α or IL-1β was added to cultured human synovial cells in an amount equivalent to that secreted from macrophages in the presence of AGE-β₂M, a significant increase in the synthesis of collagenase and morphological changes in cell shape were observed. These findings suggested that AGE-β₂M, a major component in amyloid deposits, participates in the pathogenesis of HAA as foci where monocyte/macrophage accumulate and initiate an inflammatory response that leads to bone/joint destruction.