Examining the role of transient receptor potential canonical 5 (TRPC5) in osteoarthritis

Abstract

Introduction Osteo-arthritis (OA) involves joint degradation and usually pain; with mechanisms poorly understood and few treatment options. There is evidence that the transient receptor potential canonical 5 (TRPC5) mRNA expression is reduced in OA patients’ synovia. Here we examine the profile of TRPC5 in DRG and involvement in murine models of OA. Design TRPC5 KO mice were subjected to partial meniscectomy (PMNX) or injected with monoiodoacetate (MIA) and pain-related behaviours were determined. Knee joint pathological scores were analysed and gene expression changes in ipsilateral synovium and dorsal root ganglia (DRG) determined. c-Fos protein expression in the ipsilateral dorsal horn of the spinal cord was quantified. Results TRPC5 KO mice developed a discrete enhanced pain-related phenotype. In the MIA model, the pain-related phenotype correlated with c-Fos expression in the dorsal horn and increased expression of nerve injury markers ATF3, CSF1 and galanin in the ipsilateral DRG. There were negligible differences in the joint pathology between WT and TRPC5 KO mice, however detailed gene expression analysis determined increased expression of the mast cell marker CD117 as well as extracellular matrix remodelling proteinases MMP2, MMP13 and ADAMTS4 in MIA-treated TRPC5 KO mice. TRPC5 expression was defined to sensory subpopulations in DRG. Conclusions Deletion of TRPC5 receptor signalling is associated with exacerbation of pain-like behaviour in OA which correlates with increased expression of enzymes involved in extracellular remodelling, inflammatory cells in the synovium and increased neuronal activation and injury in DRG. Together, these results identify a modulating role for TRPC5 in OA-induced pain-like behaviours.

(-)-Englerin-A Has Analgesic and Anti-Inflammatory Effects Independent of TRPC4 and 5

“…We show that EA reduced thermal and mechanical hyperalgesia in the carrageenan model. This was in accordance with previous data from this laboratory that showed that TRPC5 expression had a protective role in inflammation-and pain-related behaviour, secondary to the development of experimental arthritis [4,5]. To examine the hypothesis that TRPC5 was mediating the EA effect in vivo, we tested TRPC5 KO mice in the carrageenan model and observed that neither the anti-inflammatory nor the analgesic effects were mediated through TRPC5.…”

“…It was previously shown in TRPC5-transfected cells in culture that EA could induce the calcium uptake, in a dosedependent manner [8]. We have previously demonstrated that dorsal root ganglia express TRPC5 channels [5]. Here, we quantified the accumulation of cobalt in cultured DRG neurons induced by EA stimulation.…”

“…EA has been shown to activate TRPC4 channels and we have found that DRG neurons express TRPC4 channels [5]; thus, we hypothesised that the TRPC4 channel could be responsible for mediating EA effects in the carrageenan model. To test this hypothesis, we pre-treated 129 S1/Svlm WT mice with ML204 (4 mg/kg, i.p.…”

“…Later, TRPC5 expression was also found in joint synoviocytes where the stimulation of TRPC5 by the endogenous agonist, thioredoxin, resulted in a suppression of matrix metalloproteinases (MMPs) secretion in both human and animal synoviocytes [3]. We have previously described a role for TRPC5 in an endogenous anti-inflammatory/analgesic pathway in a model of unilateral arthritis [4], and more recently, in a model of osteoarthritis (OA) [5]. In both studies, animals lacking TRPC5 showed increased localised inflammation in the synovium characterised by the increased cellular infiltration and increased expression of pro-inflammatory mediators and extracellular remodelling enzymes, as well as enhanced synovial vascularization [4,5].…”

“…We have previously described a role for TRPC5 in an endogenous anti-inflammatory/analgesic pathway in a model of unilateral arthritis [4], and more recently, in a model of osteoarthritis (OA) [5]. In both studies, animals lacking TRPC5 showed increased localised inflammation in the synovium characterised by the increased cellular infiltration and increased expression of pro-inflammatory mediators and extracellular remodelling enzymes, as well as enhanced synovial vascularization [4,5]. Interestingly, TRPC5 expression is reduced in human synovial samples of osteoarthritis patients, compared to health post-mortem donor [4].…”