BETA-2-MICROGLOBULIN MODIFIED WITH ADVANCED GLYCATION END-PRODUCTS MODULATES COLLAGEN-SYNTHESIS BY HUMAN FIBROBLASTS

beta 2-microglobulin amyloidosis (A beta(2)m) is a serious complicatio n for patients undergoing longterm dialysis. beta 2-microglobulin modi fied with advanced glycation end products (beta(2)m-AGE) is a major co mponent of the amyloid in A beta(2)m. It is not completely understood whether beta(2)m-AGE plays an active role in the pathogenesis of A bet a(2)m, or if its presence is a secondary event of the disease. beta 2- microglobulin amyloid is mainly located in tendon and osteoarticular s tructures that are rich in collagen, and local fibroblasts constitute the principal cell population in the synthesis and metabolism of colla gen. Recent identification of AGE binding proteins on human fibroblast s lead to the hypothesis that the fibroblast may be a target for the b iological action of beta(2)m-AGE. The present study demonstrated that two human fibroblast cell lines exhibited a decrease in procollagen ty pe I mRNA and type I collagen synthesis after exposure to beta(2)m-AGE for 72 hours. Similar results were observed using AGE-modified albumi n. Antibody against the RAGE, the receptor fur AGE, attenuated this de crease in synthesis, indicating that the response was partially mediat ed by RAGE. In addition, antibody against epidermal growth factor (EGF ) attenuated the decrease in type I procollagen mRNA and type I collag en induced by beta(2)m-AGE, suggesting that EGF acts as an intermediat e factor. These findings support the hypothesis that beta(2)m-AGE acti vely participates in connective tissue and bone remodeling via a pathw ay involving fibroblast RAGE, and at least one interposed mediator, th e growth factor EGF.