Uncovering Cellular retinoic acid-binding protein 2 as a potential target for rheumatoid arthritis synovial hyperplasia

Nerea Mosquera,Antonio Mera-Varela,Antonio Gonzalez,Angela Rodriguez-Trillo,Carmen Conde

doi:10.1038/s41598-018-26027-x

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease including synovitis and synovial hyperplasia that contribute to joint destruction. Pivotal pathogenic mechanisms in this process are the dysregulated proliferation and apoptosis of fibroblast-like synoviocytes (FLS). Unfortunately, the mechanisms of FLS dysregulation are not completely elucidated. Here, we explored a new hypothesis based in the potent anti-proliferative and pro-apoptotic activity of retinoids in some types of cancer. Specifically, we investigated the role of retinoids and of the retinoic acid binding proteins, CRABP2 and FABP5, on the proliferation and apoptosis of FLS from RA by adding all-trans retinoic acid (ATRA) or silencing CRABP2 and FABP5. We showed an unconventional behaviour of RA FLS, which were relatively insensitive to ATRA. In effect, ATRA increased the resistance to apoptosis despite the high CRABP2/FABP5 ratio of RA FLS; and CRABP2 suppression sensitized RA FLS to Fas-induced apoptosis. This latter effect was associated with changes in expression of kinases, ASK1 up-regulation and ERK down-regulation, and increased phosphorylation of JNK. In addition, the potentiation of FLS apoptosis by CRABP2 silencing persisted in the presence of pro-inflammatory mediators, TNF e IL1β. Therefore, the results point to CRABP2 as a potential target to decrease synovial hyperplasia in RA.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of peripheral joints that leads to progressive destruction of cartilage and bone
We did not find significant changes in the analysis of the proliferation curve in spite of including 11 different RA lines. These results were similar to the found in control OA fibroblast-like synoviocytes (FLS) (Fig. 1A), which showed lower basal proliferation unmodified by exposure to all-trans retinoic acid (ATRA)
We have observed that this behaviour of RA FLS was not explained by a low CRABP2/fatty acid-binding protein 5 (FABP5) expression ratio, as in other cell types, but by an idiosyncratic phenotype

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of peripheral joints that leads to progressive destruction of cartilage and bone. Whereas the retinoid agonists ATRA19 and AM8020 improved the clinical and histological scores of collagen-induced arthritis (CIA) accompanied by reduction of anti-collagen antibodies in serum; the 13-cis RA pro-drug or partial agonist was ineffective[20] or increased the severity of CIA21, and the BMS-189453 antagonist reduced arthritis in the CIA and the streptococcal cell wall induced arthritis (SCWA) models[22] These discordant results remain unexplained and led us to focus on the retinoic acid binding proteins cellular RA-binding protein (CRABP2) and fatty acid-binding protein 5 (FABP5), which are known to exert divergent proliferation/survival roles in the retinoic acid pathway[23,24,25,26,27]. ATRA exacerbated FLS apoptosis resistance, making it unsuitable as drug candidate, whereas CRABP2 silencing potentiated apoptosis, making it a potential drug target

Methods

Results

Conclusion