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



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.



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).



PK2 inhibition suppressed arthritis in mice with CIA.
Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
Haruyasu
H
Ito
Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
Kentaro
K
Noda
Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
Ken
K
Yoshida
Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
Kazuhiro
K
Otani
Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
Masayuki
M
Yoshiga
Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
Yohsuke
Y
Oto
Division of Molecular Immunology, Research Center for Medical Sciences, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan.
Saburo
S
Saito
Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, Japan. d_kurosaka@jikei.ac.jp.
Daitaro
D
Kurosaka
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008811:Mice, Inbred DBA; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010082:Oxepins / Q000008:administration & dosage / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D013583:Synovial Membrane / Q000378:metabolism
C582417:1-(4-fluoro-3-methoxybenzyl)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpyrrolidine-3-carboxamide; D020533:Angiogenesis Inhibitors; D024043:Collagen Type II; D016207:Cytokines; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; D010082:Oxepins; C486586:Prok2 protein, mouse; D011759:Pyrrolidines
Collagen-induced arthritis; PKRA7; Prokineticin 2; Prokineticin antagonist; Prokineticin receptor 1; Prokineticin receptor 2