title: 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.
  
  
  CONCLUSIONS
  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.affiliation: St. Marianna University, Kawasaki, Japan.
authors.forename: G H
authors.initials: GH
authors.lastname: Yuan
authors.forename: K
authors.initials: K
authors.lastname: Masuko-Hongo
authors.forename: M
authors.initials: M
authors.lastname: Sakata
authors.forename: J
authors.initials: J
authors.lastname: Tsuruha
authors.forename: H
authors.initials: H
authors.lastname: Onuma
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: H
authors.initials: H
authors.lastname: Aoki
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.forename: K
authors.initials: K
authors.lastname: Nishioka
mesh_terms: D000368:Aged; D002356:Cartilage / Q000276:immunology / Q000378:metabolism; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D018946:Chemokine CCL5 / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D019902:Chondrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017931:DNA Primers; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology*; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C515334:CCR2 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D017931:DNA Primers; D007375:Interleukin-1; D011509:Proteoglycans; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9