Differential Effects of Interleukin-1 on Hyaluronan and Proteoglycan Metabolism in Two Compartments of the Matrix Formed by Articular Chondrocytes Maintained in Alginate

Phenotypically stable young adult bovine articular chondrocytes suspended in beads of alginate gel were first cultured for 5 days, using daily changes of medium containing 10% fetal bovine serum and supplements. The cells in the beads were then maintained in culture for a further 3 days in the presence or absence of interleukin-1α at 1 ng/ml in the daily change of medium. The exposure to interleukin-1α caused the incorporation of 35S-sulfate into the predominant cartilage proteoglycan, aggrecan, to decrease by approximately 60%. In addition, proteoglycans that had accumulated into the cell-associated matrix during the first 5 days of culture in the absence of interleukin-1α moved into the matrix further removed from the cells and from there into the medium. In contrast, the exposure to interleukin-1α was found to markedly promote the rate of synthesis of hyaluronan, especially during the first 24 h. Over the 3 days of culture in the presence of interleukin-1α, a large proportion of the newly synthesized hyaluronan molecules, as well as those that had previously become residents of the cell-associated matrix, moved out of this compartment and appeared to become permanent residents of the further removed matrix. These results demonstrate that exposure of young adult articular chondrocytes to interleukin-1α has profound effects on the metabolism of hyaluronan, a molecule that plays a critical role in the retention of proteoglycan molecules in the matrix. Importantly, the results suggest that exposure of chondrocytes to interleukin-1 in inflamed joints, such as occurs in rheumatoid arthritis, leads to the rapid loss of coordination of the synthesis of aggrecan and hyaluronan, two of the critical constituents of the proteoglycan aggregate. In addition, we present evidence that these interleukin-1-induced effects differentially alter the metabolism of hyaluronan in the metabolically active cell-associated matrix and the metabolically inactive matrix further removed from the chondrocytes.