Osteoclastic bone resorption in rheumatoid arthritis and the acute-phase response

D. O'Gradaigh, S. Bord, D. Ireland and J. E. Compston

University of Cambridge School of Clinical Medicine, Department of Medicine Bone Research Group, Cambridge, UK

Correspondence to: D. O’Gradaigh. E-mail: dogradaigh{at}camrheum.fsnet.co.uk

SIR, We read with interest the study by Hirayama et al. [1] on the formation of osteoclasts from the adherent fraction of peripheral blood mononuclear cells (PBMCs) of patients with rheumatoid arthritis. Osteoclasts can be generated from synovial macrophages, as shown by this group [2] and others [3]. Previous work has shown that macrophage infiltration of synovium correlates with radiographic progression [4], while disease remission is associated with reduction in synovial macrophages [5]. Radiographic progression also correlates with the acute-phase response over time [6]. Therefore, the findings reported in this recent study would be of particular interest if the increased resorptive activity noted by Hirayama et al. in RA patients compared with healthy controls was associated with active disease in their group of RA patients.

We have compared the in vitro generation of osteoclasts from the peripheral blood of patients with RA whose disease was either well controlled (erythrocyte sedimentation rate, ESR <25 mm/h, fewer than three tender or swollen joints) or was acutely active (ESR >25, one or more acutely inflamed joints, no evidence of infection or other systemic illness). In order to distinguish between the potential effects of the acute-phase response per se and specific effects in RA, we also generated osteoclasts from the PBMCs of patients soon after admission to the hospital with an elevated acute-phase response and conditions other than RA (e.g. respiratory tract infections, pyelonephritis). Our findings are relevant in interpreting the results of Hirayama et al. in that we found a significant correlation between the resorptive activity of in vitro generated osteoclasts and the ESR (r2 = 0.84, P < 0.001) of patients with RA. Consistent with their data, we also found no difference in osteoclast precursor frequency between patient groups. Of note, we found no significant difference in resorptive activity between osteoclasts generated from RA and from non-RA patients.

It is perhaps surprising that Hirayama et al. did not find an enhancing effect on osteoclast formation with tumour necrosis factor-{alpha} (TNF{alpha}), but noted an inhibitory effect in their RA cultures. A synergistic effect between the receptor activator of nuclear factor {kappa} B ligand (RANKL) and TNF{alpha} has been reported in a number of studies [7, 8] and in our own studies using human precursor cells [9]. This might be attributed to their use of dexamethasone in culture, and experiments without addition of dexamethasone would be of interest.

Thus, the cytokine activity of the active acute-phase response may contribute to the increased RANKL-mediated resorptive activity of osteoclasts in RA, and we respectfully submit this is an important consideration not discussed by Hirayama et al. Together, their data and ours offer a mechanistic explanation for the association between active RA and both generalized bone loss and focal joint erosion.

The authors have declared no conflicts of interest.

DO'G is supported by the Arthritis Research campaign.

References

  1. Hirayama T, Danks L, Sabokbar A, Athanasou NA. Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis. Rheumatology 2002;41:1232–9[Abstract/Free Full Text]
  2. Fujikawa Y, Sabokbar A, Neale S, Athanasou NA. Human osteoclast formation and bone resorption by monocytes and synovial macrophages in rheumatoid arthritis. Ann Rheum Dis 1996;55:816–22[Abstract]
  3. Takayanagi H, Iizuka H, Juji T et al. Involvement of receptor activator of nuclear factor {kappa}B ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 2000;43:259–69[CrossRef][ISI][Medline]
  4. Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 1996;39:115–24[ISI][Medline]
  5. Smith MD, Kraan MC, Slavotinek J et al. Treatment induced remission in rheumatoid arthritis is characterized by a reduction in macrophage content of synovial biopsies. Rheumatology 2001;40:367–74[Abstract/Free Full Text]
  6. Combe B, Dougados M, Goupille P et al. Prognostic factors for radiological progression in early rheumatoid arthritis—a multiparameter prospective study. Arthritis Rheum 2001;44:1736–43[CrossRef][ISI][Medline]
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  8. Kobayashi K, Takahashi N, Jimi E et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 2000; 191:275–85[Abstract/Free Full Text]
  9. O’Gradaigh D, Ireland D, Bord S, Beavan S, Compston J. Interaction between TNF-alpha and RANKL in osteoclastogenesis from human PBMCs [abstract]. Bone 2002;30:20s
Accepted 26 March 2003





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