Background/Purpose: Rheumatoid arthritis (RA) is a common and chronic disease associated with increased risk of developing disability. Disease remission is still rarely achieved and better treatments are needed. The fibroblast-like synoviocyte (FLS) has a central role in the formation of synovial hyperplasia and in articular damage. The FLS in vitro invasive properties through Matrigel correlate with disease severity and joint damage in rodents and patients with RA, yet, little is known about the genes regulating RA severity, FLS invasion and joint damage. We have identified significantly increased levels of the non-selective cation channel Trpv2 (transient receptor potential vanilloid subfamily, type 2 channel) in highly invasive FLS obtained from arthritis-susceptible DA rats. In this study we characterize the role of this ion channel in arthritis.

Methods: Trpv2 was knocked-down using siRNA, or was stimulated with the specific agonist O-1821, and its role in FLS invasion determined in Matrigel invasion assays over 24 hours. For the in vivo studies, C57BL/6 mice received KRN serum intra-peritoneal to induce arthritis. After the onset of arthritis animals were assigned to receive either O‑1821 or control vehicle BID.

Results: Knock-down of Trpv2 with siRNA unexpectedly significantly increased FLS invasion by nearly 4-fold suggesting that this gene is a suppressor of invasion. We next used the Trpv2-specific agonist O-1821 to treat FLS from DA rats and RA patients.  O‑1821 significantly reduced invasion by as much as 90% (p<0.01). O-1821 was then used to treat KRN serum-induced arthritis in C57BL/6 mice and it significantly reduced arthritis severity scores and preserved a nearly normal joint histology.

Conclusion: We have identified a new regulator of arthritis severity and joint damage in vivo, and show that at least part of Trpv2 activity involves suppression of the invasive properties of FLS both in rodents and patients with RA. These new discoveries should provide the basis for the development of new drugs targeting Trpv2 to better preserve joint architecture and improve outcome in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-ion-channel-trpv2-is-new-suppressor-of-arthritis-severity-and-joint-damage/