Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes

Objective: Intra-articular injection of hyaluronan (HA) has been suggested to have disease-modifying effect in osteoarthritis, but little is known about the possible mechanisms. The present study was undertaken to investigate the effects of HA with different molecular weight including 800 kDa (HA800) and 2700 kDa (HA2700) on the expression of aggrecanases, i.e. ADAMTSspecies, that play a key role in aggrecandegradation. Methods: Effects of HA species on the expression of ADAMTS1, 4, 5, 8, 9 and 15 in interleukin-1α (IL-1α)-stimulated osteoarthritic chondrocyteswere studied by RT-PCR and real-time PCR. Expression of ADAMTS4protein and aggrecanaseactivity and signal transduction pathways of IL-1, CD44and ICAM-1were examined by immunoblotting. Results: IL-1α treatment of chondrocytesinduced ADAMTS4, and HA800 and HA2700 significantly decreased the mRNA and protein expression levels of IL-1α-induced ADAMTS4. IL-1α-stimulated aggrecanaseactivity in osteoarthritic chondrocyteswas reduced by treatment with HA2700 or transfection of siRNA for ADAMTS4. A similar finding was obtained by adding HA2700 to explant culturesof osteoarthritic cartilage. HA2700 neither directly inhibited nor did it bind to ADAMTS4. Down-regulation of ADAMTS4expression with HA2700 was attenuated by treatment of IL-1α-treated chondrocyteswith anti- CD44antibody and/or anti- ICAM-1antibody. Increased phosphorylation of IL-1 receptor-associated kinase-1 (IRAK-1) and ERK1/2 by the IL-1α treatment was down-regulated by enhanced IRAK- M expressionafter HA2700 treatment. Conclusion: These data suggest that HA2700 suppresses the aggrecandegradation by down-regulation of the IL-1α-induced ADAMTS4expression through the CD44and ICAM-1signaling pathways in osteoarthritic chondrocytes.