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Prokineticin 2 antagonist, PKRA7 suppresses arthritis in mice with collagen-induced arthritis

View Article: PubMed Central - PubMed

ABSTRACT

Background: Prokineticin 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.

Methods: PK2, 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.

Results: In 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).

Conclusions: PK2 inhibition suppressed arthritis in mice with CIA.

No MeSH data available.


Related in: MedlinePlus

Changes in arthritis scores and PK2, PKR1, and PKR2 gene expression before and after the onset of arthritis. Arthritis was experimentally induced with a collagen injection on Day 21. a The severity of arthritis peaked on Day 33 and decreased thereafter. b PK2 gene expression in the joints was more elevated on Days 28 and 35 than on Day 21. c There was no significant change in PKR1 gene expression levels before and after the onset of arthritis. d PKR2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21. Values are relative to the arbitrarily assigned value of 1.0 for Day 21 and are given as means ± SEM. P values by Dunn’s multiple comparison
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Fig2: Changes in arthritis scores and PK2, PKR1, and PKR2 gene expression before and after the onset of arthritis. Arthritis was experimentally induced with a collagen injection on Day 21. a The severity of arthritis peaked on Day 33 and decreased thereafter. b PK2 gene expression in the joints was more elevated on Days 28 and 35 than on Day 21. c There was no significant change in PKR1 gene expression levels before and after the onset of arthritis. d PKR2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21. Values are relative to the arbitrarily assigned value of 1.0 for Day 21 and are given as means ± SEM. P values by Dunn’s multiple comparison

Mentions: Changes in arthritis scores in CIA mice are shown in Fig. 2a. Scores peaked on Day 33 and decreased thereafter. Real-time PCR results showed that PK2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21 (Fig. 2b; 2.15 and 2.03 versus 1.00, P = 0.0311 and P = 0.0247, respectively). PKR1 gene expression levels were similar on all days (Fig. 2c), while 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). The Spearman’s rank correlation test revealed a significant correlation between arthritis scores and relative PK2 gene expression levels with a correlation coefficient of 0.60 (Fig. 3a, P < 0.001). Arthritis scores were not correlated with PKR1 gene expression levels (Fig. 3b) but were significantly correlated with PKR2 gene expression levels (Fig. 3c, P < 0.0001).Fig. 2


Prokineticin 2 antagonist, PKRA7 suppresses arthritis in mice with collagen-induced arthritis
Changes in arthritis scores and PK2, PKR1, and PKR2 gene expression before and after the onset of arthritis. Arthritis was experimentally induced with a collagen injection on Day 21. a The severity of arthritis peaked on Day 33 and decreased thereafter. b PK2 gene expression in the joints was more elevated on Days 28 and 35 than on Day 21. c There was no significant change in PKR1 gene expression levels before and after the onset of arthritis. d PKR2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21. Values are relative to the arbitrarily assigned value of 1.0 for Day 21 and are given as means ± SEM. P values by Dunn’s multiple comparison
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Related In: Results  -  Collection

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Fig2: Changes in arthritis scores and PK2, PKR1, and PKR2 gene expression before and after the onset of arthritis. Arthritis was experimentally induced with a collagen injection on Day 21. a The severity of arthritis peaked on Day 33 and decreased thereafter. b PK2 gene expression in the joints was more elevated on Days 28 and 35 than on Day 21. c There was no significant change in PKR1 gene expression levels before and after the onset of arthritis. d PKR2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21. Values are relative to the arbitrarily assigned value of 1.0 for Day 21 and are given as means ± SEM. P values by Dunn’s multiple comparison
Mentions: Changes in arthritis scores in CIA mice are shown in Fig. 2a. Scores peaked on Day 33 and decreased thereafter. Real-time PCR results showed that PK2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21 (Fig. 2b; 2.15 and 2.03 versus 1.00, P = 0.0311 and P = 0.0247, respectively). PKR1 gene expression levels were similar on all days (Fig. 2c), while 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). The Spearman’s rank correlation test revealed a significant correlation between arthritis scores and relative PK2 gene expression levels with a correlation coefficient of 0.60 (Fig. 3a, P < 0.001). Arthritis scores were not correlated with PKR1 gene expression levels (Fig. 3b) but were significantly correlated with PKR2 gene expression levels (Fig. 3c, P < 0.0001).Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Background: Prokineticin 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.

Methods: PK2, 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&thinsp;=&thinsp;15/day). Localization of PKR1 and PKR2 proteins was examined immunohistochemically. PKRA7, a PK2 antagonist, was administered intraperitoneally for 2&nbsp;weeks to CIA mice, and the severity of arthritis was compared between treated (n&thinsp;=&thinsp;12) and untreated (n&thinsp;=&thinsp;12) mice. The gene expression levels of inflammatory cytokines IL-1&beta;, IL-6, TNF-&alpha;, and VEGF were also measured by real-time PCR and compared between treated (n&thinsp;=&thinsp;6) and untreated (n&thinsp;=&thinsp;6) CIA mice. The data was statistically analyzed, and P values of less than 0.05 were considered significant.

Results: In 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&thinsp;=&thinsp;0.0311 and 0.0247; Dunn&rsquo;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&thinsp;=&thinsp;0.002 and&thinsp;&lt;&thinsp;0.0001; Dunn&rsquo;s multiple comparison). Administration of PKRA7 suppressed the severity of arthritis (P&thinsp;&lt;&thinsp;0.001; two-way analysis of variance). A gene expression analysis of inflammatory cytokines revealed significantly reduced IL-1&beta; and lL-6 expression in the joints of PKRA7-treated mice compared to untreated mice (0.1 versus 1.0, P&thinsp;=&thinsp;0.0043 and 0.04 versus 1.0, P&thinsp;=&thinsp;0.0022, respectively; Mann-Whitney test).

Conclusions: PK2 inhibition suppressed arthritis in mice with CIA.

No MeSH data available.


Related in: MedlinePlus