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

Abstract

ObjectiveTransient 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.MethodsMale 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.ResultsAt 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.ConclusionsGenetic 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.

Synovial membrane receptors as therapeutic targets: A review of receptor localization, structure, and function

“…Finally TRPC5, which is activated by thioredoxin, has been found in like fibroblast‐like synoviocytes from RA patients …”

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

“…TRPC1/4/5 have been suggested to play multiple roles in various conditions, including epilepsy, fear, pain, severe pulmonary arterial hypertension, vascular inflammation in arthritis, and cardiac remodelling (Figure ). However, the lack of modulators to study the functional roles of these channels have limited progress into their exact role (Alawi et al, ; Camacho Londono et al, ; Francis, Xu, Zhou, & Stevens, ; Minard et al, ; Phelan et al, ; Riccio et al, ; Riccio et al, ; Westlund et al, ; Zheng & Phelan, ). The identification of high‐quality, reliable, selective, and subtype‐specific TRPC1/4/5 pharmacological tools and modulators would perhaps enable a better understanding of TRPC1/4/5 channels in human health and disease.…”

“…There have been numerous studies that have shown the involvement of TRPC channels within the cardiovascular system (Alawi et al, ; Camacho Londono et al, ; Francis et al, ; Lau et al, ; Xiao, Liu, Shen, Cao, & Li, ). Camacho Londono et al () reported that TRPC1 and TRPC4 proteins play a pivotal role in a background Ca 2+ entry pathway, which fine‐tunes Ca 2+ cycling in cardiomyocytes.…”

The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease

“…Inhibition of TRPC5 using knockouts or pharmacological agents is correlated well with the propagation of joint inflammation and hyperalgesia, providing evidence that TRCP5 is a negative regulator of inflammation. The proposed mechanism of action suggested by Alawi et al (54) is that TRPC5 acts to suppress inflammation by influencing the early cytokine-immunity axis discussed below (54). These exciting results highlight how TRP receptors protect against pain and vascular joint inflammation in arthritis.…”

“…More recently, the transient receptor potential canonical 5 (TRPC5) expressed on fibroblast like synoviocytes cells within the joint has been shown to protect against pain and inflammation in arthritic mice (54). Inhibition of TRPC5 using knockouts or pharmacological agents is correlated well with the propagation of joint inflammation and hyperalgesia, providing evidence that TRCP5 is a negative regulator of inflammation.…”