Urate crystal induced inflammation and joint pain are reduced in transient receptor potential ankyrin 1 deficient mice--potential role for transient receptor potential ankyrin 1 in gout.

Abstract

INTRODUCTION:

In gout, monosodium urate (MSU) crystals deposit intra-articularly and cause painful arthritis. In the present study we tested the hypothesis that Transient Receptor Poten-tial Ankyrin 1 (TRPA1), an ion channel mediating nociceptive signals and neurogenic in-flammation, is involved in MSU crystal-induced responses in gout by utilizing three experi-mental murine models.

METHODS:

The effects of selective pharmacological inhibition (by HC-030031) and genetic depletion of TRPA1 were studied in MSU crystal-induced inflammation and pain by using 1) spontaneous weight-bearing test to assess MSU crystal-induced joint pain, 2) subcutaneous air-pouch model resembling joint inflammation to measure MSU crystal-induced cytokine production and inflammatory cell accumulation, and 3) MSU crystal-induced paw edema to assess acute vascular inflammatory responses and swelling.

RESULTS:

Intra-articularly injected MSU crystals provoked spontaneous weight shift off from the affected limb in wild type but not in TRPA1 knock-out mice referring alleviated joint pain in TRPA1 deficient animals. MSU crystal-induced inflammatory cell infiltration and accumulation of cytokines MCP-1, IL-6, IL-1beta, MPO, MIP-1alpha and MIP-2 into subcu-taneous air-pouch (resembling joint cavity) was attenuated in TRPA1 deficient mice and in mice treated with the selective TRPA1 inhibitor HC-030031 as compared to control animals. Further, HC-030031 treated and TRPA1 deficient mice developed tempered inflammatory edema when MSU crystals were injected into the paw.

CONCLUSIONS:

TRPA1 mediates MSU crystal-induced inflammation and pain in experimental models supporting the role of TRPA1 as a potential mediator and a drug target in gout flare.

• Authors: Lauri J Moilanen, Mari Hämäläinen, Lauri Lehtimäki, Riina M Nieminen, Eeva Moilanen
• Journal: PloS one (PLoS One) Vol. 10 Issue 2 Pg. e0117770 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25658427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide
• Acetanilides
• Cytokines
• Purines
• TRPA1 Cation Channel
• Transient Receptor Potential Channels
• Trpa1 protein, mouse
• Uric Acid

Topics

• Acetanilides (pharmacology)
• Animals
• Cytokines (metabolism)
• Disease Models, Animal
• Gout (chemically induced, genetics, metabolism)
• Inflammation (chemically induced, genetics, metabolism)
• Mice
• Mice, Knockout
• Pain (chemically induced, genetics, metabolism)
• Purines (pharmacology)
• TRPA1 Cation Channel
• Transient Receptor Potential Channels (genetics, metabolism)
• Uric Acid