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Published on: February 28, 2017
Dickkopf-1 directs periosteal bone formation in two murine models of inflammatory arthritis
A T Shaw1, J Yan2, S A Kuhstoss3
1Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Objective:
The Wnt signalling antagonist Dickkopf-1 (DKK1) inhibits osteoblast differentiation and function and has been described to play a central role in promoting bone loss, while blockade of DKK1 increases bone formation. We investigated the effects of DKK1 on periosteal new bone formation in two murine models of inflammatory arthritis, the antigen-induced arthritis (AIA) and K/BxN serum transfer arthritis (STA) models.
Method:
The flare variant of AIA was induced in wild-type mice and a blocking antibody to DKK1, control rat immunoglobulin G (IgG), or phosphate-buffered saline (PBS) was administered starting on day 14, a time at which inflammation and erosions are known to be established. Knees were assessed for histological inflammation and periosteal new bone formation was quantitated. In addition, STA was generated in transgenic (Tg) mice with osteoblast-specific overexpression of Dkk1 and littermate controls. New bone formation around the wrists of these mice was quantified by micro-computed tomography.
Results:
Blockade of DKK1 in arthritic mice resulted in significantly more periosteal new bone formation compared to mice treated with control rat IgG or PBS. Conversely, in the setting of increased Dkk1 expression, arthritic Dkk1 Tg mice developed significantly less periosteal new bone than arthritic controls.
Conclusion:
DKK1 is a regulator of periosteal bone formation in inflammatory arthritis. Thus, regulation of DKK1 may be considered as a therapeutic approach in inflammatory diseases in which patients suffer from excessive periosteal bone formation, such as spondyloarthritis.
Insights
Blocking Dickkopf-1 (DKK1) enhances new bone formation in inflammatory arthritis models. Conversely, increased DKK1 expression reduces periosteal bone formation, highlighting DKK1
Area of Science:
- Bone Biology
- Inflammatory Arthritis
- Wnt Signaling Pathway
Background:
- Dickkopf-1 (DKK1) antagonizes Wnt signaling, inhibiting osteoblast function and promoting bone loss.
- DKK1 blockade has been shown to increase bone formation.
- The role of DKK1 in periosteal new bone formation during inflammatory arthritis is not fully understood.
Purpose of the Study:
- To investigate the effect of DKK1 on periosteal new bone formation in murine models of inflammatory arthritis.
- To determine if DKK1 blockade or overexpression influences bone formation in arthritis.
Main Methods:
- Utilized two murine models: antigen-induced arthritis (AIA) and K/BxN serum transfer arthritis (STA).
- Administered DKK1 blocking antibody or control IgG/PBS in AIA model.
- Assessed periosteal new bone formation via histology and micro-computed tomography.
- Generated transgenic mice with osteoblast-specific DKK1 overexpression for STA model.
Main Results:
- DKK1 blockade significantly increased periosteal new bone formation in arthritic mice.
- Conversely, arthritic mice with osteoblast-specific DKK1 overexpression exhibited significantly reduced periosteal new bone formation.
- These findings demonstrate a direct role for DKK1 in regulating periosteal bone formation during inflammation.
Conclusions:
- DKK1 is a key regulator of periosteal bone formation in the context of inflammatory arthritis.
- Targeting DKK1 may represent a therapeutic strategy for conditions characterized by excessive periosteal bone formation, such as spondyloarthritis.
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