title: Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation.
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 postmortem 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 ispilateral 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.
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.
authors.forename: Khadija M
authors.identifier: http://orcid.org/0000-0002-9208-9131
authors.initials: KM
authors.lastname: Alawi
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.
authors.forename: Fiona A
authors.identifier: http://orcid.org/0000-0002-0329-7060
authors.initials: FA
authors.lastname: Russell
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.
authors.forename: Aisah A
authors.identifier: http://orcid.org/0000-0003-3087-5150
authors.initials: AA
authors.lastname: Aubdool
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.
authors.forename: Salil
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Yanira
authors.initials: Y
authors.lastname: Riffo-Vasquez
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.
authors.forename: Lineu
authors.initials: L
authors.lastname: Baldissera
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.|Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Pratish
authors.initials: P
authors.lastname: Thakore
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.
authors.forename: Nurjahan
authors.initials: N
authors.lastname: Saleque
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.|Programa de Pós-Graduação, Universidade Ceuma, São Luís, Brazil.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Fernandes
authors.affiliation: Department of Academic Rheumatology, Arthritis Research UK Pain Centre, University of Nottingham, City Hospital, Nottingham, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Walsh
authors.affiliation: Cardiovascular Division, BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, King's College London, London, UK.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Brain
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D004487:Edema / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D013583:Synovial Membrane / Q000098:blood supply; D013585:Synovitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D007211:Indoles; C567966:ML 204; D010880:Piperidines; D012333:RNA, Messenger; D050052:TRPC Cation Channels; C491780:TRPC5 protein, human; C112021:Trpc5 protein, mouse
keywords: Arthritis; Inflammation; Synovitis