Introduction Phosphodiesterases (PDE) control the cellular concentrations of cAMP to modulate a number of cellular functions. PDE4 specific inhibitors, Apremilast and Rolipram, have demonstrated potent anti-inflammatory activity in PsA, yet their effects have not been fully elucidated in the synovium. In this study, we evaluate the effects of PDE4 inhibition on PsA synovial tissue and examine the role of miR-23a as a post-transcriptional regulator of PDE4B.
Aims To examine the expression, regulation and the disease-modifying effects of PDE4 in PsA synovial tissue.
Methods The anti-inflammatory effects of PDE4 inhibition, mediated by Rolipram, was examined in PsA synovial explant ex vivo. Synovial fibroblast outgrowths were quantified using matrigel invasion assays and pro-inflammatory mediators by ELISA and Real-time PCR. Expression of PDE4 isoforms(A-D) and miR-23a were quantified in response to TLR4 activation in ST and/or FLS. In-Silico analysis identified PDE4B as a potential target of miR-23a which was confirmed by gold-standard, luciferase reporter gene assay. MiR-23a expression was correlated to clinical markers to further elucidate its role in PsA pathogenic mechanisms.
Results PDE4 inhibition decreased the production of pro-inflammatory cytokines IL-8, IL-6, MCP1, IL-1β while increasing IL-10 expression. Furthermore, Rolipram reduced the number of explant outgrowths from synovial tissue from day 8 through to day 21. We next wanted to investigate which PDE4 isoform could be responsible for these anti-inflammatory effects and found that PDE4B displayed the highest expression at baseline and in response to LPS. To try and understand how PDE4B expression is regulated in the joint we examined the role of miR-23a which we confirmed directly targets PDE4B. A reciprocal relationship was identified between PDE4B and miR-23a in PsA FLS in response to LPS stimulation. In line with this miR-23a was found to be significantly decreased at the site of inflammation compared to OA controls and correlated with key clinical markers such as DAS-28 CRP.
Conclusions PDE4 inhibition decreases the pro-inflammatory activity of PsA synovial tissue. These actions may be mediated predominantly through the blockade of the PDE4B isoform which we found to be regulated by miR-23a. This data suggests a potential benefit for the development of PDE4B specific inhibitor for the treatment of PsA.