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

Abstract

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 protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, 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), immunochemistry, and flow cytometry on untreated or interleukin-1beta (IL-1beta)- and/or tumor necrosis factor alpha (TNFalpha)-stimulated chondrocytes. The effects of these chemokines on the expression of matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases were assayed by RT-PCR and ELISA. The effects on proteoglycan synthesis and release were also assayed, using 35S-sulfate incorporation and 35S-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 chemokine expression by IL-1beta and TNFalpha differed between normal and OA chondrocytes. Intracellular staining revealed that approximately 20% of the chondrocytes contained CCR-2 and CCR-5 in the cytoplasm, whereas cell surface expression was detected less frequently. Interestingly, RANTES induced expression of its own receptor, CCR-5, suggesting an autocrine/paracrine pathway of the chemokine within the cartilage milieu. Finally, addition of MCP-1 or RANTES not only induced MMP-3 expression, but also inhibited proteoglycan synthesis and enhanced proteoglycan release from the chondrocytes.

CONCLUSION:

The differential expression of chemokines and their receptors under the regulation of IL-1beta and TNFalpha suggests that the cytokine-triggered chemokine system may play a key role in the cartilage degradation of OA, possibly acting in an autocrine/paracrine manner.

• Authors: G H Yuan, K Masuko-Hongo, M Sakata, J Tsuruha, H Onuma, H Nakamura, H Aoki, T Kato, K Nishioka
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 44 Issue 5 Pg. 1056-70 (May 2001) ISSN: 0004-3591 [Print] United States
• PMID: 11352237 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCR2 protein, human
• Chemokine CCL2
• Chemokine CCL5
• DNA Primers
• Interleukin-1
• Proteoglycans
• RNA, Messenger
• Receptors, CCR2
• Receptors, CCR5
• Receptors, Chemokine
• Tissue Inhibitor of Metalloproteinase-1
• Tumor Necrosis Factor-alpha
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 9

Topics

• Aged
• Cartilage (immunology, metabolism)
• Chemokine CCL2 (analysis, genetics, immunology)
• Chemokine CCL5 (analysis, genetics, immunology)
• Chondrocytes (drug effects, immunology, metabolism)
• DNA Primers
• Flow Cytometry
• Gene Expression (drug effects, immunology)
• Humans
• Interleukin-1 (pharmacology)
• Matrix Metalloproteinase 3 (genetics)
• Matrix Metalloproteinase 9 (genetics)
• Middle Aged
• Osteoarthritis (immunology)
• Proteoglycans (metabolism)
• RNA, Messenger (analysis)
• Receptors, CCR2
• Receptors, CCR5 (genetics, immunology)
• Receptors, Chemokine (genetics, immunology)
• Tissue Inhibitor of Metalloproteinase-1 (genetics)
• Tumor Necrosis Factor-alpha (pharmacology)