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J. Biol. Chem., Vol. 280, Issue 13, 12310-12315, April 1, 2005

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Glucosepane Is a Major Protein Cross-link of the Senescent Human Extracellular Matrix

RELATIONSHIP WITH DIABETES^*

David R. Sell, Klaus M. Biemel¶, Oliver Reihl¶, Markus O. Lederer¶, Christopher M. Strauch, and Vincent M. Monnier||

From the Institute of Pathology and ^||Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio, 44106 and the ^¶Institut für Lebensmittelchemie (170), Universität Hohenheim, Garbenstrasse 28, Stuttgart D-70593, Germany

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.

Received for publication, January 20, 2005

^* This research was supported by Grants NIA AG18629 and NIDDK DK-57733 from the National Institutes of Health as well as a Mentorship Grant from the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Institute of Pathology, Case Western Reserve University, 2085 Adelbert Rd., Cleveland, OH, 44106. Tel.: 216-368-2930; Fax: 216-368-0495; E-mail: drs7{at}cwru.edu.

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