β2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts

beta 2-microglobulin amyloidosis (A beta(2)m) is a serious complication for patients undergoing longterm dialysis. beta 2-microglobulin modified with advanced glycation end products (beta(2)m-AGE) is a major component 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 beta(2)m, or if its presence is a secondary event of the disease. beta 2-microglobulin amyloid is mainly located in tendon and osteoarticular structures that are rich in collagen, and local fibroblasts constitute the principal cell population in the synthesis and metabolism of collagen. Recent identification of AGE binding proteins on human fibroblasts lead to the hypothesis that the fibroblast may be a target for the biological action of beta(2)m-AGE. The present study demonstrated that two human fibroblast cell lines exhibited a decrease in procollagen type I mRNA and type I collagen synthesis after exposure to beta(2)m-AGE for 72 hours. Similar results were observed using AGE-modified albumin. Antibody against the RAGE, the receptor fur AGE, attenuated this decrease in synthesis, indicating that the response was partially mediated by RAGE. In addition, antibody against epidermal growth factor (EGF) attenuated the decrease in type I procollagen mRNA and type I collagen induced by beta(2)m-AGE, suggesting that EGF acts as an intermediate factor. These findings support the hypothesis that beta(2)m-AGE actively participates in connective tissue and bone remodeling via a pathway involving fibroblast RAGE, and at least one interposed mediator, the growth factor EGF.