Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

Haynes, K. R., Pettit, A. R., Duan, R., Tseng, H. W., Glant, T. T., Brown, Matthew A, & Thomas, G. P. (2012) Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Research and Therapy, 14(6).

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Ankylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression.


PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling.


Inflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated.


This study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.

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ID Code: 87868
Item Type: Journal Article
Refereed: Yes
Additional Information: No file attached.
Keywords: collagen type 1, dickkopf 1 protein, osteocalcin, proteoglycan, Dkk1 protein, mouse, glycoprotein, signal peptide, Sost protein, mouse, animal experiment, animal model, ankylosing spondylitis, arthrodesis, article, bone mineralization, cartilage matrix, controlled study, disease course, female, gene expression profiling, immunoregulation, inflammation, intervertebral disk degeneration, mouse, nonhuman, ossification, protein expression, Wnt signaling pathway, animal, bone development, chemically induced, disease model, DNA microarray, gene ontology, genetics, human, immunohistochemistry, joint, knockout mouse, metabolism, pathology, reverse transcription polymerase chain reaction, spine, Animals, Collagen Type I, Disease Models, Animal, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Joints, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Osteogenesis, Proteoglycans, Reverse Transcriptase Polymerase Chain Reaction, Spondylitis, Ankylosing
DOI: 10.1186/ar4096
ISSN: 1478-6354
Divisions: Current > Schools > School of Biomedical Sciences
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 29 Sep 2015 04:29
Last Modified: 25 Feb 2016 04:42

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