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Dickkopf-1 is a master regulator of joint remodeling


Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-α (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodeling.

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Figure 1: DKK-1 is not relevant for the inflammatory signs of arthritis but affects the skeletal shape of joints.
Figure 2: Inhibition of DKK-1 blocks bone erosion and promotes osteophyte formation (a) Microphotographs of H&E-stained tissue sections of the joint between the calcaneus and tarsal bones in wild-type mice and hTNFtg mice treated with vehicle, anti–DKK-1 antibody (30mg/kg), anti-TNF antibody (10 mg/kg) and a combination of these antibodies at week 10.
Figure 3: New bone formation next to inflamed joints is increased upon blockade of DKK-1.
Figure 4: Increased expression of DKK-1 in arthritis is mediated by TNF-induced activation of p38MAPK signaling.
Figure 5: Expression and regulation of DKK-1 in human rheumatoid arthritis.
Figure 6: DKK-1 is critical for joint remodeling.

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We thank E. Wagner for scientific discussions and B. Tuerk and M. Tryniecki for technical assistance. We also thank G. Kollias (Alexander Fleming Biomedical Research Center) for providing hTNFtg mice, J. Behrens (University of Erlangen-Nuremberg) for providing an antibody against conductin/axin-2, A.H. Wanivenhaus (Medical University of Vienna) for human synovial tissue samples and C. Hartmann (Institute of Molecular Pathology) for the osteocalcin probe. This study was supported by the START prize of the Austrian Science Fund (G.S.) and the Deutsche Forschungsgemeinschaft (DFG; Interdisziplinäres Zentrum für Klinische Forschung Erlangen).

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Authors and Affiliations



D.Diarra conducted the in vivo analyses of hTNFtg mice and contributed to manuscript preparation. M.S. performed the analyses of collagen-induced arthritis and contributed to manuscript preparation. K.P. and J.Z. worked on the in vitro analysis of hTNFtg mice and human samples. M.S.O. performed microcomputed tomography. D. Dwyer conducted the analyses on collagen-induced arthritis. A.K. collected human samples and worked on in vitro analysis of hTNFtg mice. J.S. conducted data analyses on murine and human samples. M.H. and C.S. analyzed the GPI-induced arthritis model. D.v.d.H. and R.L. analyzed samples from spondylarthropathy patients. D.L., W.G.R. and G.S. supervised the project and contributed to manuscript preparation.

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Supplementary information

Supplementary Fig. 1

DKK-1 affects joint remodeling in collagen- and GPI- induced arthritis. (PDF 180 kb)

Supplementary Fig. 2

Regulation of DKK-1 expression and its involvement in bone metabolism. (PDF 202 kb)

Supplementary Fig. 3

The influence of OPG on the effects of DKK-1 inhibition. (PDF 295 kb)

Supplementary Fig. 4

Functional Wnt- signalling in joints after systemic blockade of DKK-1. (PDF 240 kb)

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Diarra, D., Stolina, M., Polzer, K. et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13, 156–163 (2007).

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