The role of C-C chemokines and their receptors in osteoarthritis

Objective. To evaluate the involvement of the chemokine/chemokine receptor system in cartilage degradation in osteoarthritis (OA). Methods. Expression of the 4 C-C chemokines monocyte chemoattractant protei n 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 b eta, and RANTES, and their receptors CCR-2 and CCR-5, was assessed in 11 OA patients and 5 normal controls, by reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immunochemist ry, and flow cytometry on untreated or interleukin-1 beta (IL-1 beta)- and/ or tumor necrosis factor a (TNF alpha)-stimulated chondrocytes. The effects of these chemokines on the expression of matrix metalloproteinases (MMP) a nd tissue inhibitor of metalloproteinases were assayed by RT-PCR and ELISA. The effects on proteoglycan synthesis and release were also assayed, using S-35-sulfate incorporation and S-35-proteoglycan release. Results. The C-C chemokines and their receptors CCR-2 and CCR-5 were found to be expressed in normal and OA chondrocytes. However, regulation of chemo kine expression by IL-1 beta and TNF alpha differed between normal and OA c hondrocytes. Intracellular staining revealed that similar to 20% of the cho ndrocytes contained CCR-2 and CCR-5 in the cytoplasm, whereas cell sur-face expression was detected less frequently. Interestingly, RANTES induced exp ression of its own receptor, CCR-5, suggesting an autocrine/paracrine pathw ay of the chemokine within the cartilage milieu. Finally, addition of MCP-I or RANTES not only induced MMP-3 expression, but also inhibited proteoglyc an synthesis and enhanced proteoglycan release from the chondrocytes. Conclusion. The differential expression of chemokines and their receptors u nder the regulation of IL-1 beta and TNFa suggests that the cytokine-trigge red chemokine system may play a key role in the cartilage degradation of OA , possibly acting in an autocrine/paracrine manner.