Received for publication May 17, 2007.
Revised October 17, 2007.
Accepted for publication November 14, 2007.

Regulation of Lysophosphatidic Acid Receptor Expression and Function in Human Synoviocytes: Implications for Rheumatoid Arthritis?

Abstract

Lysophosphatidic acid (LPA), via interaction with its G-protein coupled receptors, is involved in various pathological conditions. Extracellular LPA is mainly produced by the enzyme autotaxin (ATX). Using fibroblast-like synoviocytes (FLS) isolated from synovial tissues of patients with rheumatoid arthritis (RA), we studied the expression profile of LPA receptors, LPA-induced cell migration, as well as interleukin-8 (IL-8) and interleukin-6 (IL-6) production. We report that FLS express LPA receptors LPA_1-3. Moreover, exogenously applied LPA induces FLS migration and secretion of IL-8/IL-6, whereas the LPA₃ agonist OMPT stimulates cytokine synthesis but not cell motility. The LPA-induced FLS motility and cytokine production are suppressed by LPA_1/3 receptor antagonists, DGPP and VPC32183. Signal transduction through p42/44 MAPK, p38 MAPK and Rho kinase is involved in LPA-mediated cytokine secretion whereas LPA-induced cell motility requires p38 MAPK and Rho kinase but not p42/44 MAPK. Treatment of FLS with TNF- increases LPA₃ mRNA expression, and correlates with enhanced LPA- or OMPT-induced cytokine production. LPA-mediated super-production of cytokines by TNF--primed FLS is abolished by LPA_1/3 receptor antagonists. We also report the presence of ATX in synovial fluid of RA patients. The synovial fluid-induced cell motility is reduced by LPA_1/3 receptor antagonists and ATX inhibitors. Together the data suggest that LPA₁ and LPA₃ may contribute to the pathogenesis of RA, through the modulation of FLS migration and cytokine production. The above results provide novel insights into the relevance of LPA receptors in FLS biology and as potential therapeutic targets for the treatment of RA.

Key words: Tumor necrosis factor, Protein Kinases (other), Cdc42, rho, rac, other small G proteins, MAP Kinase, P38 MAP Kinase, Regulation of gene expression

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