Remodeling of Age- and Diabetes-Related Changes in Extracellular Matrix





R.C. deGroof

Alteon Inc., 170 Williams Drive, Ramsey, NJ 07446, USA



There is broad evidence that, over time, advanced glycation endproducts (AGE) accumulate in extracellular matrix and lead to loss of function in affected tissues. AGE forms nonenzymatic crosslinks in collagen. These crosslinks are implicated in many complications of diabetes (retinopathy, neuropathy, nephropathy, heart failure) as well as skin aging and amyloid plaque formation. AGE formation is associated with a combination of time of exposure to serum glucose, oxidative stress, hypertension, and uremia, among others.

AGE and nonenzymatic crosslinks are demonstrated to signal inflammatory cytokines, extracellular matrix expansion, angiogenesis, and growth factors. Reduction of the formation of AGE by pharmacologic intervention decreases the rate of progression of these complications of aging and diabetes. A novel crosslink breaker, ALT-711 (4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride) reverses extracellular matrix expansion, leading to down regulation of inflammatory cytokines and growth factors in a variety of animal models of aging and diabetes, as well as in humans with cardiovascular disease.




Key words: extracellular matrix, AGE, collagen, crosslink, ALT-711







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