MIA-INDUCED INFLAMMATION AND JOINT PAIN ARE REDUCED IN TRPA1 DEFICIENT MICE - POTENTIAL ROLE FOR TRPA1 IN OSTEOARTHRITIS

Purpose: Injection of monosodium iodoacetate (MIA) into a murine joint is a widely used experimental model of osteoarthritis (OA). MIA induces an acute inflammation which leads to destruction of articular cartilage, to hyperalgesia and to decreased weight bearing on the affected limb indicative for pain. Like in the OA, the detailed mechanisms related to the onset and progression of MIA-induced experimental OA are not understood thoroughly. However, on cellular level MIA has been recognized to inhibit glyceraldehyde-3-phosphate leading to production of reactive oxygen species (ROS) and to activation of caspases and inflammatory gene expression. Transient Receptor Potential Ankyrin 1 (TRPA1) is an ion channel known to mediate nociceptive signals and neurogenic inflammation. It is activated by various environmental pungent compounds but also by molecules produced in inflammation such as ROS. In the present study we tested the hypothesis that TRPA1 is involved in MIA-induced acute inflammation and joint pain. Methods: The effects of pharmacological inhibition (by TCS 5861528) and genetic depletion of TRPA1 were studied in MIA-induced inflammation and joint pain (weight-bearing test) in mouse models. In addition, the effect of MIA was studied in human primary OA chondrocytes and in mouse cartilage. Results: Intra-articularly injected MIA provoked spontaneous weight shift away from the affected limb in wild type but not in TRPA1 knock-out mice referring alleviated joint pain in TRPA1 deficient animals. Interestingly, mice treated with the selective TRPA1 antagonist TCS 5861528 as well as TRPA1 deficient mice developed tempered inflammatory response when MIA was injected into the paw indicating that TRPA1 is involved in the mechanisms of MIA-induced acute inflammation. Also, the levels of substance P were diminished in TRPA1 KO mice and in mice treated with the TRPA1 antagonist, and the MIA-induced acute response was attenuated by pre-treatment with the neurokinin 1 receptor antagonist L703,606. Further, cultured human primary OA chondrocytes expressed TRPA1. Co-stimulation with MIA and IL-1β increased COX-2 expression which was inhibited by a selective TRPA1 antagonist, and COX-2 expression was also lower in the cartilage from TRPA1 knock-out than wild type mice. Conclusions: TRPA1 mediates MIA-induced inflammation and pain in experimental models supporting the role of TRPA1 as a potential mediator and drug target in OA.