AbstractAlterations in the integrity of the extracellular matrix play an important role in osteoarthritis. Matrix crosslinks in articular cartilage of the knee were studied in partially meniscectomized rabbits to compare changes due to osteoarthritis with those occurring during aging. Pyridinoline, a lysyl oxidase‐initiated crosslink, and pentosidine, a crosslink formed by the Maillard/glycation reaction, were assayed separately on reverse‐phase high performance liquid chromatography. A significant increase in the percentage of insoluble collagen was observed in normal 12‐month‐old rabbits compared with the levels in 3‐month‐old animals, whereas osteoarthritis was associated with a shift toward more soluble fractions. Total pyridinoline content did not change with age or osteoarthritis. Total pentosidine, however, increased significantly with age but remained constant with osteoarthritis. Analysis of the distribution of crosslinks among solubility fractions indicated a significant shift of pyridinoline from the pepsin‐released fraction to the insoluble fraction with osteoarthritis, but no changes were observed with age. Pentosidine distribution shifted toward the pepsin‐released fraction in osteoarthritis, with a shift toward the insoluble fraction with age. Because of the low levels of pentosidine present, its precise location, whether collagenous or noncollagenous, remains unclear. However, since pentosidine represents a marker for the overall Maillard reaction, the results of our studies support a role for Maillard reaction products in the aging of extracellular matrix. The shift of pentosidine toward more soluble fractions suggests the presence of matrix degradation and repair in