Owen W F, Hou F F, Stuart R O, Kay J, Boyce J, Chertow G M, Schmidt A M
Department of Medicine, Brigham & Women's Hospital Harvard Medical School, Boston, Massachusetts, USA.
Kidney Int. 1998 May;53(5):1365-73. doi: 10.1046/j.1523-1755.1998.00882.x.
Beta 2-microglobulin amyloidosis (A beta 2m) is a serious complication for patients undergoing long-term dialysis. beta 2-microglobulin modified with advanced glycation end products (beta 2m-AGE) is a major component of the amyloid in A beta 2m. It is not completely understood whether beta 2m-AGE plays an active role in the pathogenesis of A beta 2m, or if its presence is a secondary event of the disease. beta 2-microglobulin amyloid is mainly located in tendon and osteo-articular 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 2m-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 2m-AGE for 72 hours. Similar results were observed using AGE-modified albumin. Antibody against the RAGE, the receptor for 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 2m-AGE, suggesting that EGF acts as an intermediate factor. These findings support the hypothesis that beta 2m-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.
β2-微球蛋白淀粉样变性（Aβ2m）是长期透析患者的一种严重并发症。经晚期糖基化终产物修饰的β2-微球蛋白（β2m-AGE）是Aβ2m淀粉样蛋白的主要成分。β2m-AGE在Aβ2m发病机制中是否发挥积极作用，或者其存在是否是该疾病的继发事件，目前尚未完全明确。β2-微球蛋白淀粉样蛋白主要位于富含胶原蛋白的肌腱和骨关节结构中，局部成纤维细胞是胶原蛋白合成和代谢的主要细胞群体。最近在人成纤维细胞上鉴定出AGE结合蛋白，由此提出成纤维细胞可能是β2m-AGE生物学作用靶点的假说。本研究表明，两种人成纤维细胞系在暴露于β2m-AGE 72小时后，I型前胶原mRNA和I型胶原合成减少。使用AGE修饰的白蛋白也观察到了类似结果。抗AGE受体RAGE的抗体减弱了这种合成减少，表明该反应部分由RAGE介导。此外，抗表皮生长因子（EGF）抗体减弱了β2m-AGE诱导的I型前胶原mRNA和I型胶原的减少，提示EGF作为中间因子发挥作用。这些发现支持了β2m-AGE通过涉及成纤维细胞RAGE和至少一种中间介质生长因子EGF的途径积极参与结缔组织和骨重塑的假说。
