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

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.

All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes

“…No previous study has analyzed the role of ATRA, or any other retinoid, in the RA FLS except for our previous work that was restricted to FLS proliferation and survival. FLSs' proliferation was insensitive to ATRA, whereas their resistance to apoptosis was exacerbated (Mosquera et al, 2018). The inhibitory effects of ATRA on FLS migration and invasion observed in the current study were in concordance with that found in cancerous and nonmalignant cells.…”

“…Therefore, there is a growing interest in developing treatments aimed to revert the activated phenotype of RA FLS (Niedermeier et al, 2010). Recently, we found that a transporter of retinoids, cellular retinoic acid binding protein 2, is a candidate drug target of this type because cellular retinoic acid binding protein 2 suppression reverts RA FLS resistance to apoptosis (Mosquera et al, 2018). In the same study, we observed unconventional responses of RA FLS to the main biologic retinoid, all-trans retinoic acid.…”

“…We have analyzed whether the treatment with ATRA could reduce the migration ability of RA FLS using a cell wound-healing assay. We used the dose of 5 mM ATRA based on previous literature (Chen and Stallings, 2007;Das et al, 2010Das et al, , 2013Foley et al, 2011;García-Regalado et al, 2013) and our previous work (Mosquera et al, 2018). When the FLS cells were cultured with ATRA, the healed area was reduced to about half the control at 96 hours (P , 0.01, Fig.…”

“…The beneficial effect of ATRA was observed at the supraphysiological dose of 5 mM, which has been frequently used in in vitro studies (Chen and Stallings, 2007;Das et al, 2010Das et al, , 2013Foley et al, 2011;García-Regalado et al, 2013;Mosquera et al, 2018) and broadly corresponds to the ATRA concentrations attainable with the doses used to markedly supress collagen-induced arthritis in DBA mice (Kwok et al, 2012). In effect, the 0.5 mg/kg of ATRA given to these mice leads to peak ATRA concentrations between 0.6 and 3 mM in serum and tissues, as estimated from the available data in mice (Jing et al, 2017).…”

“…In the same study, we observed unconventional responses of RA FLS to the main biologic retinoid, all-trans retinoic acid. These results prompted us to investigate further the effects of alltrans retinoic acid (ATRA) on the activated phenotype of RA FLS (Mosquera et al, 2018).…”