Prokineticin 2 antagonist, PKRA7 suppresses arthritis in mice with collagen-induced arthritis
Haruyasu Ito1, Kentaro Noda1, Ken Yoshida1
1Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
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.
Insights
Prokineticin 2 (PK2) inhibition significantly reduced arthritis severity in a mouse model of rheumatoid arthritis. This suggests PK2 is a potential therapeutic target for inflammatory joint diseases.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Prokineticin 2 (PK2) is upregulated in collagen-induced arthritis (CIA), a model for rheumatoid arthritis.
- Investigating PK2's role is crucial for understanding and treating inflammatory joint conditions.
Purpose of the Study:
- To evaluate the therapeutic potential of inhibiting PK2 in a mouse model of CIA.
- To analyze the impact of PK2 inhibition on arthritis severity and inflammatory markers.
Main Methods:
- Real-time PCR was used to measure PK2, PKR1, and PKR2 mRNA in CIA mouse joints.
- Immunohistochemistry identified PKR1 and PKR2 protein localization.
- PK2 antagonist PKRA7 was administered to CIA mice to assess arthritis suppression.
- Gene expression of inflammatory cytokines (IL-1β, IL-6, TNF-α, VEGF) was quantified.
Main Results:
- PK2 and PKR2 gene expression increased significantly in CIA mouse joints over time.
- PKR1 and PKR2 proteins were localized to neutrophils and macrophages, respectively.
- PKRA7 treatment significantly suppressed arthritis severity (P < 0.001).
- PKRA7 administration markedly reduced IL-1β and IL-6 expression in the joints.
Conclusions:
- PK2 inhibition effectively suppresses arthritis in the CIA mouse model.
- Targeting the PK2 pathway represents a promising therapeutic strategy for rheumatoid arthritis.
- Further research into PK2's role in inflammatory arthritis is warranted.
