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Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation

Alawi, Khadija M.; Russell, Fiona A.; Aubdool, Aisah A.; Srivastava, Salil; Riffo-Vasquez, Yanira; Baldissera, Lineu; Thakore, Pratish; Saleque, Nurjahan; Fernandes, Elisabeth S.; Walsh, David A.; Brain, Susan D.

Authors

Khadija M. Alawi

Fiona A. Russell

Aisah A. Aubdool

Salil Srivastava

Yanira Riffo-Vasquez

Lineu Baldissera

Pratish Thakore

Nurjahan Saleque

Elisabeth S. Fernandes

David A. Walsh

Susan D. Brain



Abstract

Objective: Transient receptor potential canonical 5 (TRPC5) is functionally expressed on a range of cells including fibroblast-like synoviocytes, which play an important role in arthritis. A role for TRPC5 in inflammation has not been previously shown in vivo. We investigated the contribution of TRPC5 in arthritis.
Methods: Male wild-type and TRPC5 knockout (KO) mice were used in a complete Freund’s adjuvant (CFA)-induced unilateral arthritis model, assessed over 14 days. Arthritis was determined by measurement of knee joint diameter, hindlimb weightbearing asymmetry and pain behaviour. Separate studies involved chronic pharmacological antagonism of TRPC5 channels. Synovium from human post-mortem control and inflammatory arthritis samples were investigated for TRPC5 gene expression.
Results: At baseline, no differences were observed. CFA-induced arthritis resulted in increased synovitis in TRPC5 KO mice assessed by histology. Additionally, TRPC5 KO mice demonstrated reduced ipsilateral weightbearing and nociceptive thresholds (thermal and mechanical) following CFA-induced arthritis. This was associated with increased mRNA expression of inflammatory mediators in the ipsilateral synovium and increased concentration of cytokines in synovial lavage fluid. Chronic treatment with ML204, a TRPC5 antagonist, augmented weightbearing asymmetry, secondary hyperalgesia and cytokine concentrations in the synovial lavage fluid. Synovia from human inflammatory arthritis demonstrated a reduction in TRPC5 mRNA expression.
Conclusions: Genetic deletion or pharmacological blockade of TRPC5 results in an enhancement in joint inflammation and hyperalgesia. Our results suggest that activation of TRPC5 may be associated with an endogenous anti-inflammatory/analgesic pathway in inflammatory joint conditions.

Journal Article Type Article
Publication Date Feb 28, 2017
Journal Annals of the Rheumatic Diseases
Print ISSN 0003-4967
Electronic ISSN 1468-2060
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
Volume 76
Issue 1
Pages 252-260
APA6 Citation Alawi, K. M., Russell, F. A., Aubdool, A. A., Srivastava, S., Riffo-Vasquez, Y., Baldissera, L., …Brain, S. D. (2017). Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation. Annals of the Rheumatic Diseases, 76(1), 252-260. https://doi.org/10.1136/annrheumdis-2015-208886
DOI https://doi.org/10.1136/annrheumdis-2015-208886
Publisher URL http://ard.bmj.com/content/76/1/252
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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