Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors
Open Access
- 1 January 2012
- journal article
- Published by Springer Science and Business Media LLC in Arthritis Research & Therapy
- Vol. 14 (6), R253
- https://doi.org/10.1186/ar4096
Abstract
Introduction\ud \ud 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.\ud \ud Methods\ud \ud PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling.\ud \ud Results\ud \ud 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.\ud \ud Conclusions\ud \ud 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 processThis publication has 47 references indexed in Scilit:
- Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibilityNature Genetics, 2011
- Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspectsArthritis Research & Therapy, 2011
- Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han ChineseAnnals Of The Rheumatic Diseases, 2010
- IFN-γ Regulates the Requirement for IL-17 in Proteoglycan-Induced ArthritisThe Journal of Immunology, 2009
- Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritisArthritis & Rheumatism, 2009
- Th1/Th17 polarization and acquisition of an arthritogenic phenotype in arthritis-susceptible BALB/c, but not in MHC-matched, arthritis-resistant DBA/2 miceInternational Immunology, 2009
- lumi: a pipeline for processing Illumina microarrayBioinformatics, 2008
- Overexpression of tumor necrosis factor causes bilateral sacroiliitisArthritis & Rheumatism, 2004
- Osteocrin, a Novel Bone-specific Secreted Protein That Modulates the Osteoblast PhenotypeOnline Journal of Public Health Informatics, 2003
- Impaired On/Off Regulation of TNF Biosynthesis in Mice Lacking TNF AU-Rich Elements: Implications for Joint and Gut-Associated ImmunopathologiesImmunity, 1999