Gillespie, J, Ross, RL, Corinaldesi, C et al. (7 more authors) (2018) Transforming Growth Factor β Activation Primes Canonical Wnt Signaling Through Down-Regulation of Axin-2. Arthritis & Rheumatology, 70 (6). pp. 932-942. ISSN 2326-5191
Abstract
Methods: Canonical Wnt signaling activation was analyzed by TOPflash T cell factor/lymphoid enhancer factor promoter assays. Axin‐2 was evaluated in vitro by analysis of Axin‐2 primary/mature transcript expression and decay, TGFβ receptor type I (TGFβRI) blockade, small interfering RNA–mediated depletion of tristetraprolin 1, and XAV‐939–mediated Axin‐2 stabilization. In vivo, Axin‐2 messenger RNA (mRNA) and protein expression was determined in skin and lung biopsy samples from mice that express a kinase‐deficient TGFβRII specifically on fibroblasts (TβRIIΔk‐fib–transgenic mice) and from littermate controls.
Results: SSc fibroblasts displayed an increased response to canonical Wnt ligands despite basal levels of Wnt signaling that were comparable to those in healthy control fibroblasts in vitro. Notably, we showed that SSc fibroblasts had reduced basal expression of Axin‐2, which was caused by an endogenous TGFβ–dependent increase in Axin‐2 mRNA decay. Accordingly, we observed that TGFβ decreased Axin‐2 expression both in vitro in healthy control fibroblasts and in vivo in TβRIIΔk‐fib–transgenic mice. Additionally, using Axin‐2 gain‐ and loss‐of‐function experiments, we demonstrated that the TGFβ‐induced increased response to Wnt activation characteristic of SSc fibroblasts depended on reduced bioavailability of Axin‐2.
Conclusion: This study highlights the importance of reduced bioavailability of Axin‐2 in mediating the increased canonical Wnt response observed in SSc fibroblasts. This novel mechanism extends our understanding of the processes involved in Wnt/β‐catenin–driven pathology and supports the rationale for targeting the TGFβ pathway to regulate the aberrant Wnt signaling observed during fibrosis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018, American College of Rheumatology. This is the post-peer reviewed version of the following article: Gillespie, J, Ross, RL, Corinaldesi, C et al. (7 more authors) (2018) Transforming Growth Factor β Activation Primes Canonical Wnt Signaling Through Down-Regulation of Axin-2. Arthritis & Rheumatology, 70 (6). pp. 932-942, which has been published in final form at https://doi.org/10.1002/art.40437. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Haematology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Clinical Musculoskeletal Medicine (LIRMM) (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 09 Aug 2018 14:05 |
Last Modified: | 08 Apr 2019 12:11 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/art.40437 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:134248 |