Beta 2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts.
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.
Owen
W F
WF
Department of Medicine, Brigham & Women's Hospital Harvard Medical School, Boston, Massachusetts, USA. wfowen@bics.bwh.harvard.edu
Hou
F F
FF
Stuart
R O
RO
Kay
J
J
Boyce
J
J
Chertow
G M
GM
Schmidt
A M
AM
D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism; D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism* / Q000494:pharmacology
D000906:Antibodies; D017127:Glycation End Products, Advanced; D007375:Interleukin-1; D011347:Procollagen; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D001613:beta 2-Microglobulin; D004815:Epidermal Growth Factor; D003094:Collagen