SAT0051 Examining the role of trpc5 in osteoarthritis pain
Authors: J. Sousa-Valente, F. Ayaz, X. Kodji, S.D. Brain
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Transient receptor potential canonical 5 (TRPC5) is a cation channel that putatively acts as a sensor of one or more chemical factors but the exact biology is not fully known. It was recently found to be expressed in fibroblast-like synoviocytes where TRPC5 activation by endogenous thioredoxin – which has been shown to be elevated in synovial fluid of patients with rheumatoid arthritis – results in the suppression of matrix metalloproteinases secretion.<sup>1</sup> Genetic deletion or pharmacological blockade of TRPC5 receptor in arthritic mice resulted in marked exacerbation of hyperalgesia and critically increased localised inflammation in the synovium, characterised by increased cellular infiltration, secretion of early response cytokines and enhanced synovial vascularisation.<sup>2</sup> Interestingly, in this study, mRNA expression of TRPC5 was reduced in inflamed human arthritis samples particularly in the synovium from patients with osteoarthritis (OA), highlighting a potential role for TRPC5 in OA. <h3>Objectives</h3> With the aim to investigate putative mechanisms mediated by TRPC5 signalling in OA pain, we have examined the development of monoiodoacetate (MIA)-referred mechanical hypersensitivity and joint pathology in wild type and mice carrying a TRPC5 deletion. <h3>Methods</h3> Wild type and TRPC5 knock-out (TRPC5) mice were intra-articularly injected with 0.75 mg of MIA, and hind-paw mechanical thresholds and weight bearing changes were assessed at regular intervals up to 28 days. Knee joint histo chemical analysis of cartilage degradation using toluidine blue staining and synovial inflammation using haematoxylin and eosin staining was also performed. <h3>Results</h3> Both TRPC5 KO and WT mice developed referred mechanical hypersensitivity following MIA injection, however the onset was faster (day 3 vs day 10) in TRPC5 KO mice. By the end of the study, at 28 days after MIA injection, mechanical hypersensitivity had reached similar levels in TRPC5 KO and WT mice. Moreover, at a 0.7 mg MIA dose administered, TRPC5 KO, but not WT mice developed weight bearing asymmetries over the course of the study and most significantly from 14 to 28 days after MIA injection. In paraformaldehyde-fixed joints obtained 28 days post MIA injection from TRPC5 KO and WT mice no significant differences in cartilage degradation or inflammatory content were observed. <h3>Conclusions</h3> This study suggests that deletion of the TRPC5 receptor signalling is associated with a faster onset of referred allodynia and increased guarding/on-going pain like behaviour in a model of OA. <h3>References</h3> [1] Xu SZ, Sukumar P, Zeng F, Li J, Jairaman A, English A, et al. TRPC channel activation by extracellular thioredoxin. Nature2008;451(7174):69–72. [2] Alawi KM, Russell FA, Aubdool AA, Srivastava S, Riffo-Vasquez Y, Baldissera L, Jr, et al. Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation. Ann Rheum Dis2017;76(1):252–60. <h3>Acknowledgements</h3> This project was supported by ARUK. <h3>Disclosure of Interest</h3> None declared