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-alpha (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.
Diarra
Danielle
D
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany.
Stolina
Marina
M
Polzer
Karin
K
Zwerina
Jochen
J
Ominsky
Michael S
MS
Dwyer
Denise
D
Korb
Adelheid
A
Smolen
Josef
J
Hoffmann
Markus
M
Scheinecker
Clemens
C
van der Heide
Desiree
D
Landewe
Robert
R
Lacey
Dave
D
Richards
William G
WG
Schett
Georg
G
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D001862:Bone Resorption / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000032:analysis; D006801:Humans; D007118:Immunoassay; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013582:Synovial Fluid / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D016207:Cytokines; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; D015675:Osteocalcin