title: Stimulatory effects of advanced glycation endproducts (AGEs) on fibronectin matrix assembly.
abstract: Advanced glycation endproducts (AGEs) are a heterogeneous group of compounds that form via non-enzymatic glycation of proteins throughout our lifespan and at a higher rate in certain chronic diseases such as diabetes. AGEs contribute to the progression of fibrosis, in part by stimulating cellular pathways that affect gene expression. Long-lived ECM proteins are targets for non-enzymatic glycation but the question of whether the AGE-modified ECM leads to excess ECM accumulation and fibrosis remains unanswered. In this study, cellular changes due to AGE accretion in the ECM were investigated. Non-enzymatic glycation of proteins in a decellularized fibroblast ECM was achieved by incubating the ECM in a solution of methylglyoxal (MGO). Mass spectrometry of fibronectin (FN) isolated from the glycated matrix identified twenty-eight previously unidentified MGO-derived AGE modification sites including functional sites such as the RGD integrin-binding sequence. Mesangial cells grown on the glycated, decellularized matrix assembled increased amounts of FN matrix. Soluble AGE-modified bovine serum albumin (BSA) also stimulated FN matrix assembly and this effect was reduced by function-blocking antibodies against the receptor for AGE (RAGE). These results indicate that cells respond to AGEs by increasing matrix assembly and that RAGE is involved in this response. This raises the possibility that the accumulation of ECM during the progression of fibrosis may be enhanced by cell interactions with AGEs on a glycated ECM.
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544-1014, USA.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Pastino
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544-1014, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Greco
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544-1014, USA.
authors.forename: Rommel A
authors.initials: RA
authors.lastname: Mathias
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544-1014, USA.
authors.forename: Ileana M
authors.initials: IM
authors.lastname: Cristea
authors.affiliation: Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544-1014, USA. Electronic address: jschwarz@princeton.edu.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schwarzbauer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002417:Cattle; D002461:Cell Line, Transformed; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D005353:Fibronectins / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D011765:Pyruvaldehyde / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: C000593874:Ager protein, rat; D057134:Antibodies, Neutralizing; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D016023:Integrins; D009842:Oligopeptides; D000067759:Receptor for Advanced Glycation End Products; D012710:Serum Albumin, Bovine; D011765:Pyruvaldehyde; C047981:arginyl-glycyl-aspartic acid
keywords: Advanced glycation endproducts; Extracellular matrix; Fibronectin; Mass spectrometry; Non-enzymatic glycation; RAGE