Dickkopf-1 directs periosteal bone formation in two murine models of inflammatory arthritis

Abstract

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.

Acknowledgements

We would like to thank Lilly Research Laboratories for providing the anti-DKK-1 antibody and rat IgG, and Dr Henry Kronenberg for the gift of Dkk1 Tg mice. KRN T-cell transgenic mice were kindly provided by Drs Benoist and Mathis, Harvard Medical School, Boston, MA, USA, and Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France.

Disclosure statement

JFC and EG receive author royalties from Up To Date, Inc. EG receives royalties from the textbook Rheumatology and salary from The New England Journal of Medicine. EG has consulted for Eli Lilly and received grant funding from AbbVie; JFC has served on advisory boards for Ultragenyx. All other authors have declared no conflicts of interest.

Supplemental data

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by grants from the National Institutes of Health [R01-AR055952 to EG, K08 AR062590 to JFC]; the Rheumatology Research Foundation and the Department of Orthopedics [JFC].