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• Comment on “G. Schett et al., Tumour necrosis factor blockers and structural remodelling in ..
  Frank P Luyten
  Published on: 8 June 2007

• Published on: 8 June 2007

  Comment on “G. Schett et al., Tumour necrosis factor blockers and structural remodelling in ..

  • Frank P Luyten, MD PhD
  • Other Contributors:
    • Rik J. Lories (KU Leuven), Kurt de Vlam (KU Leuven), Dennis McGonagle (Academic Unit of the Musculoskeletal Diseases, University of Leeds, United Kingdom)

  Dear Editor, we read with interest the editorial by Schett et al. on structural remodeling in ankylosing spondylitis. [1] We acknowledge the effort to highlight potential differences between ankylosing spondylitis and rheumatoid arthritis but would like to underline a number of critical issues. Most importantly, the authors did not distinguish the process of new cartilage and bone formation at the enthesis as seen in the di...

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  Dear Editor, we read with interest the editorial by Schett et al. on structural remodeling in ankylosing spondylitis. [1] We acknowledge the effort to highlight potential differences between ankylosing spondylitis and rheumatoid arthritis but would like to underline a number of critical issues. Most importantly, the authors did not distinguish the process of new cartilage and bone formation at the enthesis as seen in the different forms of spondyloarthritis from osteophyte formation in osteoarthritis that typically occurs at the borderzone between articular cartilage and bone. [2,3] The enthesis and its residing cell populations appear to be the primary anatomical target site in spondyloarthritis but in their editorial, Schett et al seem to pay little attention to the specific anatomic localization of tissue formation and remodeling. [4,5] We believe this may have important consequences for the molecular pathways involved in these processes and the therapeutic targeting thereof. We haveused an animal model of joint ankylosis starting from the enthesis to investigate the cell and molecular biology of this process. [6] We have demonstrated that new bone formation in this model is predominantly endochondral ossification. In addition, inhibition of bone orphogenetic proteins (BMP) using overexpression of noggin, a BMP antagonist, has a profound effect on both incidence and severity of arthritis and ankylosingenthesitis in preventive and therapeutic experiments. Biopsy specimens from ankylosing enthesitis in patients seem to support these molecular findings. [7] Based on these data, we have put forward the hypothesis that inflammation and structural remodeling of the joint in diseases such as ankylosing spondylitis and psoriatic arthritis are likely to be at least partially independent events. [7,8,9] This was confirmed by the lack of effect of tumour necrosis factor inhibition in this model.[10] Indeed, we demonstrated that etanercept did not inhibit structural changes at the enthesis, findings that now appear to be supported by preliminary human cohort data.[11]

  We agree with the authors that WNT signaling may also be an importantpathway in these processes. However, the presence of DKK-1 in erosions in man and mice suggests that DKK-1 inhibits WNT-stimulated direct, not endochondral, bone formation and erosion repair.[12] The data in the TNF-transgenic model also show that DKK-1 has an inhibitory effect on osteophyte formation.[13] However, in our view, the role of Wnt signaling in entheseal changes remains to be studied. In particular it is noteworthy that WNT signaling also has inhibitory effects on chondrogenesis and chondrocyte maturation and may therefore favor membranous rather than endochondral bone formation.[14,15] In addition, differences in serum DKK-1 levels between rheumatoid arthritis and ankylosing spondylitis patients may reflect differences in systemic inflammation. Establishing a hierarchy of tissue formation pathways in this context and their interactions with inflammatory and tissue destructive mechanisms therefore remains a major challenge to better understand mechanisms of disease in spondyloarthritis.

  References

  (1) Schett G, Landewe R, van der HD. Tumour necrosis factor blockersand structural remodelling in ankylosing spondylitis: what is reality and what is fiction? Ann Rheum Dis 2007;66:709-711.

  (2) Benjamin M, McGonagle D. The anatomical basis for disease localisation in seronegative spondyloarthropathy at entheses and related sites. J Anat 2001;199:503-526.

  (3) Lories RJ, Luyten FP. Bone morphogenetic proteins in destructive and remodeling arthritis. Arthritis Res Ther 2007;9:207.

  (4) Ball J. Enthesopathy of rheumatoid and ankylosing spondylitis. Ann Rheum Dis 1971;30:213-223.

  (5) McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998;352:1137-1140.

  (6) Lories RJ, Matthys P, Derese I, De Vlam K, Luyten FP. Ankylosing enthesitis, dactylitis and onychoperiostitis in a mouse model of psoriatic arthritis. Ann Rheum Dis 2004;63:595-598.

  (7) Lories RJU, Derese I, Luyten FP. Modulation of Bone Morphogenetic Protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest 2005;115:1571-1579.

  (8) Luyten FP, Lories RJ, Verschueren P, De Vlam K, Westhovens R. Contemporary concepts of inflammation, damage and repair in rheumatic diseases. Best Pract Res Clin Rheumatol 2006;20:829-848.

  (9) De Vlam K, Lories RJ, Luyten FP. Mechanisms of Pathologic New Bone Formation. Curr Rheumatol Rep 2006;8:332-337.

  (10) Lories RJ, Derese I, De Bari C, Luyten FP. Evidence for uncoupling of inflammation and joint remodeling in a mouse model of Spondyloarthritis. Arthritis Rheum 2006;56:489-497.

  (11) van der Heijde DM, Landewe R, Ory P, Vosse D, Zhou L, Tsuji W et al. Two-year etanercept therapy does not inhibit radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis 2006;65[Suppl. II]: 81.

  (12) Walsh NC, Manning CA, Boch JA, Iwata K, Condon KW, McHugh KP et al. Wnt Signaling Antagonists Are Candidates For The Suppression Of Osteoblast Differentiation In Inflammatory Arthritis. Arthritis Rheum 2006;54[9]:S511.

  (13) Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007;13:156-163.

  (14) Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 2005;8:739-750.

  (15) Lories RJ, Peeters J, Bakker A, Derese I, Tylzanowski P, Schrooten J, Thomas JT, Luyten FP. Deletion of Frzb affects articular cartilage and biomechanical properties of the long bones Arthritis Rheum (in press).

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  Conflict of Interest:
  None declared.

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