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Papers In Press, published online ahead of print January 26, 2005
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106
Corresponding Author: drs7{at}po.cwru.edu
The extracellular matrix (ECM) 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 ECM 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, methylgloxal, 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 yrs were 2000, 30, and 15 pmol/mg for glucospane, MODIC and GODIC, respectively. Diabetes, but not renal failure, increased glucosepane to 5000 pmol/mg, (P<0.0001) and all others (< 60 pmol/mg, P<0.01). In GBMs, glucosepane reached up to 500 pmol/mg collagen and was increased in diabetes (P<0.0001) but not old age. In conclusion, glucosepane is the single major crosslink 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.
J. Biol. Chem, 10.1074/jbc.M500733200
Submitted on January 20, 2005
Revised on January 26, 2005
Accepted on January 26, 2005
Glucosepane is a major protein cross-link of the senescent human extracellular matrix. Relationship with diabetes
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