Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints

TY - JOUR

T1 - Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints

AU - Uderhardt, S

AU - Diarra, D

AU - Katzenbeisser, J

AU - David, J-P

AU - Zwerina, J

AU - Richards, W

AU - Kronke, G

AU - Schett, G

PY - 2010/3/1

Y1 - 2010/3/1

N2 - OBJECTIVE: To study whether Dickkopf (DKK)-1, an inhibitor of wingless (Wnt) signalling, is involved in the fusion of sacroiliac joints.METHODS: Mice transgenic for tumour necrosis factor (TNFtg mice), which develop bilateral sacroiliitis, were treated with vehicle, anti-TNF antibody or anti-DKK1 antibody. Sacroiliac joints were analysed for histological signs of inflammation, bone erosion, osteoclast formation and ankylosis. Moreover, expression of collagen type X, beta-catenin and DKK-1 was assessed by immunohistochemistry.RESULTS: There were no signs of spontaneous ankylosis of the sacroiliac joints in TNFtg mice. TNF blockade effectively reduced inflammation, bone erosion and osteoclast numbers in the sacroiliac joints, but did not lead to ankylosis. Blockade of DKK1 had no effect on inflammatory signs of sacroiliitis, but significantly reduced bone erosions and osteoclast counts. Moreover, DKK1 blockade promoted expression of collagen type X, the formation of hypertrophic chondrocytes and ankylosis of sacroiliac joints.CONCLUSION: DKK1 influences inflammatory remodelling of sacroiliac joints by prevention of joint ankylosis. This may indicate an important role of the Wnt signalling pathway in the structural bone changes of axial joint disease. Although this model does not reflect the entire spectrum of ankylosing spondylitis in humans, it helps to explain the pathophysiological processes of sacroiliac joint ankylosis, which is a hallmark of the spondyloarthritides.

AB - OBJECTIVE: To study whether Dickkopf (DKK)-1, an inhibitor of wingless (Wnt) signalling, is involved in the fusion of sacroiliac joints.METHODS: Mice transgenic for tumour necrosis factor (TNFtg mice), which develop bilateral sacroiliitis, were treated with vehicle, anti-TNF antibody or anti-DKK1 antibody. Sacroiliac joints were analysed for histological signs of inflammation, bone erosion, osteoclast formation and ankylosis. Moreover, expression of collagen type X, beta-catenin and DKK-1 was assessed by immunohistochemistry.RESULTS: There were no signs of spontaneous ankylosis of the sacroiliac joints in TNFtg mice. TNF blockade effectively reduced inflammation, bone erosion and osteoclast numbers in the sacroiliac joints, but did not lead to ankylosis. Blockade of DKK1 had no effect on inflammatory signs of sacroiliitis, but significantly reduced bone erosions and osteoclast counts. Moreover, DKK1 blockade promoted expression of collagen type X, the formation of hypertrophic chondrocytes and ankylosis of sacroiliac joints.CONCLUSION: DKK1 influences inflammatory remodelling of sacroiliac joints by prevention of joint ankylosis. This may indicate an important role of the Wnt signalling pathway in the structural bone changes of axial joint disease. Although this model does not reflect the entire spectrum of ankylosing spondylitis in humans, it helps to explain the pathophysiological processes of sacroiliac joint ankylosis, which is a hallmark of the spondyloarthritides.

KW - Animals

KW - Antibodies, Monoclonal

KW - Antirheumatic Agents

KW - Arthritis, Experimental

KW - Collagen Type X

KW - Immunohistochemistry

KW - Intercellular Signaling Peptides and Proteins

KW - Mice

KW - Mice, Transgenic

KW - Sacroiliac Joint

KW - Tumor Necrosis Factor-alpha

KW - beta Catenin

U2 - 10.1136/ard.2008.102046

DO - 10.1136/ard.2008.102046

M3 - SCORING: Journal article

C2 - 19304568

VL - 69

SP - 592

EP - 597

JO - ANN RHEUM DIS

JF - ANN RHEUM DIS

SN - 0003-4967

IS - 3

ER -