The first objective of my work was to use the ank/ank (progressive ankylosis) mutant mice, which have a deficiency in inorganic pyrophosphate transport, to address the role of Ank in joint ankylosis. I observed the presence of hypertrophic chondrocytes in the uncalcified ank/ank mice articular cartilage. This novel phenotype is likely due to a dysregulation of chondrocyte maturation as these chondrocytes expressed hypertrophic chondrocyte markers (collagen type X and tissue non-specific alkaline phosphatase). I also showed by immunohistochemical staining that beta-catenin expression was upregulated and localized in the nuclei of articular ank/ank chondrocytes, suggesting activation of Wnt/beta-catenin signaling in these chondrocytes.
The second objective was to use ank/ank mice as an informative model for understanding ankylosis mechanisms in human ankylosing spondylitis (AS) patients, as WNT/beta-catenin signaling plays an important role in ankylosis in AS patients. We attempted rescue of joint ankylosis in ank/ank mice by gene transfer of noggin, an antagonist of BMP signaling. Paradoxically, noggin-treated ank/ank mice had accelerated ankylosis, as evidenced by joint pathology and IHC staining of beta-catenin showed more intense signals in the spinal chondrocytes of the treated mice. As noggin and sclerostin (an antagonist of beta-catenin signaling) form a mutually inhibitory complex, we hypothesize that the formation of this complex results in relieving suppression of both beta-catenin and BMP signaling, leading to more severe ankylosis in ank/ank mice.
By quantitative molecular imaging, I have demonstrated that ankylosis in these mutant mice developed simultaneously in distal and axial joint, instead of being a centripetal process.
In summary, I have made three original observations in the ank/ank mice: the hypertrophic chondrocyte phenotype; activation of beta-catenin signaling and the simultaneous development of ankylosis in distal and axial joints. These mutant mice serve as valuable model for pre-clinical studies which enable modeling and testing of novel anti-ankylosis treatments.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26466 |
| Date | 08 March 2011 |
| Creators | Las Heras, Facundo |
| Contributors | Inman, Robert D. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0049 seconds