MiR-146a-5p Expression in Peripheral CD14+ Monocytes from Patients with Psoriatic Arthritis Induces Osteoclast Activation, Bone Resorption, and Correlates with Clinical Response

Abstract

In psoriatic arthritis (PsA), progressive bone destruction is mediated by monocyte-derived osteoclasts. MicroRNAs (miRNAs) regulate many pathophysiological processes; however, their function in PsA patient monocytes has not been examined. This study aims to address whether specific miRNAs in CD14+ monocytes and monocyte-derived osteoclasts cause active osteoclastogenesis in PsA patients. Candidate miRNAs related to monocyte activation (miR-146a-5p, miR-146b-5p and miR-155-5p) were measured in circulatory CD14+ monocytes collected from 34 PsA patients, 17 psoriasis without arthritis (PsO) patients, and 34 normal controls (NCs). CD14+ monocytes were cultured with media containing TNF-α and RANKL to differentiate into osteoclasts. Osteoclast differentiation and bone resorption were measured by TRAP immunostaining and dentin slice resorption, respectively. The results showed that the miR-146a-5p expression was higher in PsA patient-derived CD14+ monocytes compared to PsO and NCs. Activation and bone resorption were selectively enhanced in osteoclasts from PsA patients, but both were abrogated by RNA interference against miR-146a-5p. More importantly, after clinical improvement using biologics, the increased miR-146a-5p expression in CD14+ monocytes from PsA patients was selectively abolished, and associated with blood CRP level. Our findings indicate that miR-146a-5p expression in CD14+ monocytes derived from PsA patients correlates with clinical efficacy, and induction of osteoclast activation and bone resorption.

Serum MicroRNA Signature as a Diagnostic and Therapeutic Marker in Patients with Psoriatic Arthritis

“…However, further experiments are required to elucidate the pathogenic mechanism of action of miR-21-5p in PsA pathogenesis. In support of the observations made in the present study, recent reports demonstrate elevated expression of miR-146a-5p in CD14+ monocytes from patients with PsA compared to both psoriasis patients and HC 35 , and that a single-nucleotide polymorphism in the miR-146a gene was associated with the progression of PsA 36 , an association that appears to be functional in patients with PsA but not RA 37 . Further, in terms of therapeutic response, elevated serum levels of miR-130a-3p in patients with ovarian cancer have been associated with therapeutic resistance to cisplatin 38 , which is consistent with other reports in glioblastoma patients and their response to a temazolamide treatment regimen 6 .…”

Identification of the Key Molecular Drivers of Phosphorus Utilization Based on Host miRNA-mRNA and Gut Microbiome Interactions

“…The current study shows the role of miRNAs in linking transcripts enriched in bone metabolism and immune functions. Many miRNAs are known to regulate bone metabolism, host-microbiome interaction, and inflammatory and immune processes [16,28,29]. MiR-146a affects osteoblast and osteoclast formation in vitro and in vivo miR-146a+/− mice [16,30].…”

Upregulation of miR-941 in Circulating CD14+ Monocytes Enhances Osteoclast Activation via WNT16 Inhibition in Patients with Psoriatic Arthritis

“…In addition, we demonstrate that the increased miR-941 expression in CD14+ monocytes from PsA patients enhances osteoclast formation potential and active resorption activity. Our previous study reported that miR-146a-5p expression in CD14+ monocytes of PsA patients correlates with clinical efficacy and inducts osteoclast activation and bone resorption [ 11 ]. In this study, the overall microRNAs were measured using NGS study.…”

“…Then, 3 × 10 5 purified human CD14+ monocytes were seeded in 24-well plates containing a-MEM with FBS (10%, v / v ; Invitrogen, Waltham, MA, USA) and M-CSF (20 ng/mL; PeproTech, Rocky Hill, NJ, USA) for three days. RANKL (100 ng/mL; PeproTech, Rocky Hill, NJ, USA) and TNF-α (100 ng/mL; PeproTech, Rocky Hill, NJ, USA) were added to induce osteoclast differentiation [ 11 ]. The osteoclasts were stained with tartrate-resistant acid phosphatase (TRAP) at day 13 using the Acid Phosphate Leukocyte Kit (Sigma, St. Louis, MO, USA) according to the manufacturer’s instructions.…”

“…With a hypothesis-driven approach, we previously investigated the role of three common osteoclast activation microRNAs (miR-146a/b and miR-155) in CD14+ monocytes in PsA. We demonstrated miR-146a-5p in CD14+ monocytes from PsA patients correlates with its disease severity in vivo and active bone resorption in vitro [ 11 ]. However, in that study, only three microRNAs are investigated in osteoclasts of PsA patients.…”