Transient Receptor Potential Ankyrin 1 (TRPA1) Is Involved in Upregulating Interleukin-6 Expression in Osteoarthritic Chondrocyte Models.

Mari Hämäläinen,Lauri J Moilanen,Elina Nummenmaa,Eeva Moilanen,Teemu Moilanen,Riina M Nieminen,Katriina Vuolteenaho,Antti Pemmari,Lauri Tuure

doi:10.3390/ijms22010087

Abstract

Transient receptor potential ankyrin 1 (TRPA1) is a membrane-bound ion channel found in neurons, where it mediates nociception and neurogenic inflammation. Recently, we have discovered that TRPA1 is also expressed in human osteoarthritic (OA) chondrocytes and downregulated by the anti-inflammatory drugs aurothiomalate and dexamethasone. We have also shown TRPA1 to mediate inflammation, pain, and cartilage degeneration in experimental osteoarthritis. In this study, we investigated the role of TRPA1 in joint inflammation, focusing on the pro-inflammatory cytokine interleukin-6 (IL-6). We utilized cartilage/chondrocytes from wild-type (WT) and TRPA1 knockout (KO) mice, along with primary chondrocytes from OA patients. The results show that TRPA1 regulates the synthesis of the OA-driving inflammatory cytokine IL-6 in chondrocytes. IL-6 was highly expressed in WT chondrocytes, and its expression, along with the expression of IL-6 family cytokines leukemia inhibitory factor (LIF) and IL-11, were significantly downregulated by TRPA1 deficiency. Furthermore, treatment with the TRPA1 antagonist significantly downregulated the expression of IL-6 in chondrocytes from WT mice and OA patients. The results suggest that TRPA1 is involved in the upregulation of IL-6 production in chondrocytes. These findings together with previous results on the expression and functions of TRPA1 in cellular and animal models point to the role of TRPA1 as a potential mediator and novel drug target in osteoarthritis.

Highlights

Transient receptor potential ankyrin 1 (TRPA1) is a membrane-associated cation channel
We have recently shown that in monosodium iodoacetate (MIA)-induced experimental osteoarthritis, TRPA1 activation has a role in mediating inflammation, cartilage degradation and joint pain [19]
We have shown that TRPA1 is expressed in primary human osteoarthritic chondrocytes, and that its expression is downregulated by the antiinflammatory drugs aurothiomalate and dexamethasone [8,20]

Summary

Introduction

Transient receptor potential ankyrin 1 (TRPA1) is a membrane-associated cation channel. The amount of inflammatory and catabolic mediators increases, while the production of cartilage matrix components decreases [15] It is not known what initiates this process, but the main inflammatory mediators driving OA pathogenesis are believed to be IL-1β, tumor necrosis factor (TNF)-α, and according to recent studies, IL-6 [16,17,18]. These cytokines are produced by synovial cells and by chondrocytes, and they support OA-associated inflammation and cartilage destruction by stimulating the production of matrix degrading enzymes such as matrix metalloproteinases (MMPs) and aggrecanases, as well as pro-inflammatory cytokines and other inflammatory factors including nitric oxide and eicosanoids [15]

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