Reply

M. D. Smith

Rheumatology Research Unit, Repatriation General Hospital, Daws Road, Daw Park, South Australia 5041, Australia

E-mail: malcolm.smith{at}rgh.sa.gov.au

Harashima et al. produce some interesting results concerning OPG and RANKL mRNA production by RA and OA synovial fibroblasts. Unfortunately, there are several reasons why it is difficult to relate the results of Harashima et al. to the results presented in our recent paper [1].

No clinical details are provided on the RA or OA patients other than a statement that the RA patients are ‘active’. It would be helpful to know about disease duration, previous and current treatment, joint scores and levels of inflammatory markers.

All the results from Harashima et al. relate to mRNA production, and no evidence is presented to show that this mRNA results in OPG and RANKL protein production.

In addition, all the results relate to type II synovial fibroblasts grown in tissue culture; there are no results relating to other relevant inflammatory cell synovial infiltrates. Our immunohistochemical labelling results show that the major sources of OPG protein are type I synovial macrophages and endothelial cells [1], while the major source of RANKL protein was the lymphocyte [2]. We were unable to demonstrate significant OPG or RANKL protein production by type I synoviocytes by immunohistochemistry on synovial tissue.

Finally, the effects of tumour necrosis factor-{alpha} (TNF-{alpha}) on OPG and RANKL mRNA production shown by Harashima et al. are not very impressive and do not appear to correlate with the clinical situation. These authors suggest that TNF-{alpha} treatment of RA fibroblasts increased OPG mRNA and decreased RANKL mRNA, yet the active RA synovial fibroblasts (in a clinical situation in which increased TNF-{alpha} is expected in the synovial membrane) showed lower OPG and higher RANKL mRNA levels than OA fibroblasts. In addition, this would suggest that anti-TNF treatments would decrease OPG mRNA and increase RANKL mRNA levels in synovial fibroblasts, leading to a situation in which bone erosion should be increased. This is not what clinical trials on anti-TNF treatment have suggested [3].

Perhaps the conclusion that can be drawn is that results from studies undertaken in in vitro cell culture systems on isolated cell populations from synovial tissue do not necessarily correlate with what is seen in vivo in whole-tissue systems and should be interpreted with caution.

References

  1. Haynes D, Barg E, Crotti T et al. Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathies and osteoarthritis and normal controls. Rheumatology 2003;42:123–34.[Free Full Text]
  2. Crotti TN, Smith MD, Weedon H et al. Receptor activator NF-kB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 2002;61:1047–54.[Abstract/Free Full Text]
  3. Bathon JM, Martin RW, Fleischmann RM et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93.[Abstract/Free Full Text]
Accepted 25 July 2003





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