Abstract
BackgroundProkineticin 2 (PK2) expression is upregulated in mice with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. The purpose of our study was to investigate the effects of PK2 inhibition on CIA.MethodsPK2, prokineticin receptor (PKR) 1, and PKR2 mRNA transcripts in the joints of CIA mice were measured by real-time PCR on Days 21, 28, and 35 (n = 15/day). Localization of PKR1 and PKR2 proteins was examined immunohistochemically. PKRA7, a PK2 antagonist, was administered intraperitoneally for 2 weeks to CIA mice, and the severity of arthritis was compared between treated (n = 12) and untreated (n = 12) mice. The gene expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α, and VEGF were also measured by real-time PCR and compared between treated (n = 6) and untreated (n = 6) CIA mice. The data was statistically analyzed, and P values of less than 0.05 were considered significant.ResultsIn the thickened synovial membrane, PKR1 protein was expressed in infiltrating neutrophils, while PKR2 expression was found in macrophage-like mononuclear cells. PK2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21 (2.15 and 2.03 versus 1.00, P = 0.0311 and 0.0247; Dunn’s multiple comparison). PKR2 gene expression levels were significantly higher on Days 28 and 35 compared to Day 21 (25.4 and 39.3 versus 1.0, P = 0.002 and < 0.0001; Dunn’s multiple comparison). Administration of PKRA7 suppressed the severity of arthritis (P < 0.001; two-way analysis of variance). A gene expression analysis of inflammatory cytokines revealed significantly reduced IL-1β and lL-6 expression in the joints of PKRA7-treated mice compared to untreated mice (0.1 versus 1.0, P = 0.0043 and 0.04 versus 1.0, P = 0.0022, respectively; Mann-Whitney test).ConclusionsPK2 inhibition suppressed arthritis in mice with CIA.
Highlights
Prokineticin 2 (PK2) expression is upregulated in mice with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis
In light of the fact that angiogenesis plays an important role in the pathogenesis of rheumatoid arthritis [13, 14], we previously investigated PK2 expression in mice with collageninduced arthritis (CIA), the animal model of rheumatoid arthritis, and reported that PK2 gene expression was significantly elevated in the joints of CIA mice and correlated with the severity of the arthritis [15]
prokineticin receptor 1 (PKR1) gene expression levels were similar on all days (Fig. 2c), while prokineticin receptor 2 (PKR2) gene expression levels were significantly higher on Days 28 and 35 compared to Day 21 (Fig. 2d; 25.4 and 39.3 versus 1.0, P = 0.002 and P ≤ 0.0001, respectively)
Summary
Prokineticin 2 (PK2) expression is upregulated in mice with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. In light of the fact that angiogenesis plays an important role in the pathogenesis of rheumatoid arthritis [13, 14], we previously investigated PK2 expression in mice with collageninduced arthritis (CIA), the animal model of rheumatoid arthritis, and reported that PK2 gene expression was significantly elevated in the joints of CIA mice and correlated with the severity of the arthritis [15]. Such upregulation of PK2 has been reported in a rat testitis model [16], a mouse model of inflammatory colitis [17], and a mouse model with autoimmune encephalomyelitis [18]. These findings point to PK2’s role in various inflammatory diseases
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