Background/Purpose:  Psoriatic Arthritis (PsA) is a chronic immune-mediated inflammatory disease, characterised by proliferation of synovial tissue and progressive destruction of articular cartilage/bone associated with psoriasis. These processes may be governed by microRNA (miRNA), a class of small non-coding RNAs which exert their function through suppression of specific target genes. Altered miR-23a expression has been previously associated with angiogenic and pro-inflammatory mechanisms in other diseases. To date, altered miRNA expression and regulation has not been examined in PsA.

Methods:  Synovial tissue biopsies were obtained under direct visualisation from site of inflammation by needle arthroscopy, along with peripheral blood mononuclear cells (PBMC) from PsA (n=8), osteoarthritis (OA) (n=7), and healthy controls (n=8). To examine possible factors involved in regulating miRNA expression, primary PsA synovial fibroblasts (SFC) were isolated and cultured with candidate pro-inflammatory stimuli including TLR ligands: Pam3CSK4 (1 µg/ml), LPS (1 µg/ml), polyIC (10 µg/ml) and pro-inflammatory cytokines: IL-1β (1 ng/ml), TNFα (10 ng/ml) and IL-17 (20ng/ml). Total RNA was extracted using the Qiagen miRNeasy kit, and expression of miR-23a was measured by Sybr Green real-time PCR.  In parallel, IL-6, IL-8 and MCP-1 were quantified in culture supernatants by ELISA. Clinical demographics such as CRP, TJC, SJC and patient global were also assessed. 

Results:  A significant increase in miR-23a expression was demonstrated in PsA PBMC versus OA (p=0.0476) and HC (p=0.0186). In contrast, a significant decrease in miR-23a expression was observed in PsA synovial tissue compared to OA (p=0.0172). In PsA, synovial miR-23a expression negatively correlated with matched PBMC miR-23a (r=-1.00, p=0.0167), demonstrating a dissociation in miR-23a expression between systemic and local inflammation. Furthermore, miR-23a expression in PsA synovial biopsies inversely correlated with DAS28-CRP (r= -0.5294, p=0.035). TLR activation via PolyIC (TLR3) and LPS (TLR4) significantly decreased miR-23a expression in primary PsA SFC (all p<0.05), with no effect observed for pro-inflammatory cytokines. This was paralleled by a significant induction of IL-6, IL-8 and MCP-1 in response to LPS and PolyIC (all p<0.05). Finally, in silico analysis identified putative targets for miR-23a including PDE4B and PTK2B, which are known to be involved in multiple immune pathways, osteoclast function and angiogenic mechanisms.

Conclusion:  This is the first report of altered expression and regulation of miRNA in PsA, levels of which were inversely associated with increased joint inflammation. MiR-23a may be an important regulator of pathogenesis in PsA and may represent a potential target for therapeutic strategies. Further work will examine the functional role of miR-23a and it’s implications on disease pathogenesis in PsA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/negative-regulator-mir-23a-down-regulated-in-psoriatic-arthritis-implications-for-disease-pathogenesis/