Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Role of Liver X Receptors In the Regulation of Effector Functions of Fibroblast-Like Synoviocytes In Rheumatoid Arthritis.
Arce-Franco1, M.Teresa, Dominguez-Luis2, M. Jesus, Diaz-Martin2, Ana, Herrera-Garcia3, Ada, Miranda-Carus4, Maria Eugenia, Bustabad-Reyes3, Sagrario, Castrillo5, Antonio
Rheumatology Service, La Laguna, Spain
Hospital Universitario de Canarias, La Laguna, Spain
Hospital Universitario de Canarias, La Laguna. Tenerife, Spain
La Paz Hospital. IdiPaz, Madrid, Spain
University of Las Palmas de Gran Canaria (ULPGC), Canary Islands, Las Palmas (Gran Canaria), Spain
Fibroblast-like synoviocytes (FLS) play an essential role as effector cells in the pathogenesis of rheumatoid arthritis (RA) through the proliferation, production of metalloproteinases (MMPs) and invasion of joint structures. However, until now none therapeutic approach has been designed to target FLS in RA. The liver X receptors (LXR) isoforms, a and b are members of the nuclear receptor superfamily of transcription factors activated by ligand. LXR-induced genes were mainly identified as genes involved in reverse cholesterol transport but several evidences suggest that they are also involved in the modulation of the inflammatory response. The main objective of this work was to study the presence of LXR subtypes and the implication of LXR agonists in the migration, proliferation and MMPs production by FLS from RA patients.
Six FLS cell lines were isolated by enzymatic dispersion of synovial membrane and cultured in DMEM high glucose from 6 RA patients undergoing knee replacement prosthesis. The presence of LXR isoforms on cultured FLS was studied by RT-PCR and Western Blot. Quantitative RT-PCR of ATP binding cassette A1 (ABCA1) and ABCG1, two LXR target genes, was used to determine the functional capability of LXR on FLS in response to the LXR synthetic agonists: T1317 and GW3965. The role of LXR in FLS chemotaxis was determined by two-compartment transwell assay. Cell growth was measured by a fluorescence-based proliferation assay. Collagenase activity was determined by a fibril degradation assay.
FLS from patients with RA expressed in basal conditions both mRNA and protein of a and b isoforms of LXR. The LXR synthetic agonists T1317 and GW3965 induced ABCA1 and ABCG1 genes in FLS by qRT-PCR. FLS cultured in the presence of both LXR agonists showed a reduction in their proliferative capacity of 40±5% respect to the absence of agonists with or without TNF-a. In transwell experiments using SDF-1 as chemoattractant, both LXR agonists significantly inhibited in 40±7% the migration of cells. FLS cultured with TNF-a in the presence of LXR agonists showed a reduction in the expression of MMP-1 and MMP-9 of 2.5 and 12 times, respectively ((-DDCt) method). Similarly, the collagenase activity induced by TNF-a in FLS supernatant decreased significantly (65±10%) by the presence of GW3965 respect to basal conditions.
FLS from RA patients express constitutively functional LXR. Agonists of these receptors show antiproliferative activity, reduce migration and MMP production in FLS. Taken together, these data suggest that LXR may be a potential therapeutic target for the control of synovitis in patients with RA.
To cite this abstract, please use the following information:
Arce-Franco, M.Teresa, Dominguez-Luis, M. Jesus, Diaz-Martin, Ana, Herrera-Garcia, Ada, Miranda-Carus, Maria Eugenia, Bustabad-Reyes, Sagrario, et al; Role of Liver X Receptors In the Regulation of Effector Functions of Fibroblast-Like Synoviocytes In Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1818