Previous studies have shown that fibrous collagen undergoes intermolecular cross-linking at multiple sites of the elongated triple-helical regions among adjacent juxtaposed collagen molecules on incubation with a very high concentration of reducing sugar such as 200 mM ribose, and the similarity of the changes in its physicochemical properties to that of senescent collagen aged in vivo has been emphasized. In the present study, however, it was found that when incubated with less than 30 mM ribose, fibrous collagen underwent intermolecular cross-linking primarily between the telopeptide region of a collagen molecule and the triple-helical region of another adjacent collagen molecule, and intermolecular cross-linking between the triple-helical regions of adjacent collagen molecules was very small. Physiological significance of the previous studies thus needs to be reevaluated. (C) 2015 Elsevier Inc. All rights reserved.