Production of the chemokine RANTES by articular chondrocytes and role in cartilage degradation

Objective. To examine the expression of the chemokine RANTES and its recept ors in normal and osteoarthritic (OA) human cartilage and to analyze its ef fects on chondrocyte function. Methods. The expression of RANTES and its receptors were examined by revers e transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry . The effect of RANTES on gene expression of other cytokines and on the rel ease of mediators of cartilage degradation was also examined by PCR and enz yme-linked immunosorbent assay. Results. The expression of RANTES was undetectable in normal chondrocytes u ntil after stimulation with interleukin-1 beta (IL-1 beta) or IL-18. Cultur es of normal cartilage also produced RANTES in response to IL-1 beta, as de monstrated by immunohistochemistry. All OA cartilage samples analyzed expre ssed RANTES messenger RNA (mRNA); RANTES protein was detected by immunohist ochemistry in the superficial and mid zones of the tissue. OA chondrocytes produced elevated levels of RANTES constitutively and after IL-1 beta stimu lation. Normal cartilage expressed the RANTES receptors CCR3 and CCR5, but not CCR1. CCR1 was expressed in OA cartilage, and CCR3 and CCR5 were increa sed. In normal chondrocytes, RANTES induced the expression of inducible nit ric oxide synthase and IL-6. RANTES stimulated the release of matrix metall oproteinase 1 in normal and OA chondrocytes as effectively as IL-1 beta. Tr eatment of normal articular cartilage with RANTES increased the release of glycosaminoglycans and profoundly reduced the intensity of Safranin O stain ing. Conclusion. Chondrocytes produce RANTES and express RANTES receptors. RANTE S and CCR5 were markedly increased in OA and after in vitro treatment of no rmal chondrocytes with IL-1. Chondrocyte activation and cartilage degradati on were identified as novel biologic and pathogenetic activities of this ch emokine.