title: Glucosepane is a major protein cross-link of the senescent human extracellular matrix. Relationship with diabetes.
abstract: The extracellular matrix in most tissues is characterized by progressive age-related stiffening and loss of proteolytic digestibility that are accelerated in diabetes and can be duplicated by the nonenzymatic reaction of reducing sugars and extracellular matrix proteins. However, most cross-links of the Maillard reaction described so far are present in quantities too low to account for these changes. Here we have determined in human skin and glomerular basement membrane (GBM) collagen the levels of the recently discovered lysine-arginine cross-links derived from glucose, methylglyoxal, glyoxal, and 3-deoxyglucosone, i.e. glucosepane, MODIC, GODIC, and DOGDIC, respectively. Insoluble preparations of skin collagen (n = 110) and glomerular basement membrane (GBM, n = 28) were enzymatically digested, and levels were measured by isotope dilution technique using liquid chromatography/mass spectrometry. In skin, all cross-links increased with age (p < 0.0001) except DOGDIC (p = 0.34). In nondiabetic controls, levels at 90 years were 2000, 30, and 15 pmol/mg for glucosepane, MODIC, and GODIC, respectively. Diabetes, but not renal failure, increased glucosepane to 5000 pmol/mg (p < 0.0001), and for all others, increased it to <60 pmol/mg (p < 0.01). In GBMs, glucosepane reached up to 500 pmol/mg of collagen and was increased in diabetes (p < 0.0001) but not old age. In conclusion, glucosepane is the single major cross-link of the senescent extracellular matrix discovered so far, accounting for up to >120 mole% of triple helical collagen modification in diabetes. Its presence in high quantities may contribute to a number of structural and cell matrix dysfunctions observed in aging and diabetes.
authors.affiliation: Institute of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA. drs7@cwru.edu
authors.forename: David R
authors.initials: DR
authors.lastname: Sell
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Biemel
authors.forename: Oliver
authors.initials: O
authors.lastname: Reihl
authors.forename: Markus O
authors.initials: MO
authors.lastname: Lederer
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Strauch
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000737:chemistry; D001381:Azepines / Q000737:chemistry* / Q000378:metabolism*; D001485:Basement Membrane / Q000378:metabolism; D016922:Cellular Senescence; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D011485:Protein Binding; D012044:Regression Analysis; D051437:Renal Insufficiency / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D013997:Time Factors
chemical_list: C403511:2-ammonio-6-((2-((4-ammonio-5-oxido-5--oxopentyl)amino)-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene)amino)hexanoate; C403510:2-ammonio-6-((2-((4-ammonio-5-oxido-5-oxopentyl)amino)-4,5-dihydro-1H-imidazol-5-ylidene)amino)hexanoate; D001381:Azepines; D003432:Cross-Linking Reagents; D007093:Imidazoles; C432392:N(6)-(2-((4-ammonio-5-oxido-5-oxopentyl)amino)-5-(2,3,4-trihydroxybutyl)3,5-dihydro-4H-imidazol-4-ylidene)lysinate; C432394:N(6)-(5,6,7,8,8a-pentahydro-2-(4-amino-4-carboxybutyl)azepino(2,3-d)imidazol-4-yl)lysinate; D003094:Collagen; D001120:Arginine; D008239:Lysine