Stimulatory effects of advanced glycation endproducts (AGEs) on fibronectin matrix assembly.

TitleStimulatory effects of advanced glycation endproducts (AGEs) on fibronectin matrix assembly.
Publication TypeJournal Article
Year of Publication2017
AuthorsPastino, AK, Greco, TM, Mathias, RA, Cristea, IM, Schwarzbauer, JE
JournalMatrix Biol
Date Published2017 May
KeywordsAmino Acid Sequence, Animals, Antibodies, Neutralizing, Cattle, Cell Line, Transformed, Extracellular Matrix, Fibronectins, Fibrosis, Gene Expression, Glycation End Products, Advanced, Humans, Integrins, Mesangial Cells, Mice, Models, Biological, NIH 3T3 Cells, Oligopeptides, Pyruvaldehyde, Rats, Receptor for Advanced Glycation End Products, Serum Albumin, Bovine, Signal Transduction

<p>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.</p>

Alternate JournalMatrix Biol
PubMed ID27425255
PubMed Central IDPMC5237628
Grant ListR01 CA160611 / CA / NCI NIH HHS / United States
P41 EB001046 / EB / NIBIB NIH HHS / United States
R01 GM114141 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
T32 EB005583 / EB / NIBIB NIH HHS / United States