Decreased semaphorin3A expression correlates with disease activity and histological features of rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is an autoimmune disease of which the pathogenetic mechanisms are not fully understood. Semaphorin3A (Sema3A) has an immune regulatory role. Neuropilin1 (NRP1), the primary receptor for Sema3A, is also a receptor for vascular endothelial growth factor 165 (VEGF 165). It has been shown that Sema3A competitively antagonizes VEGF 165 signaling. This study investigated whether Sema3A is expressed in synovial tissues, and is associated with disease activity and the histological features of synovial tissues from RA patients.


METHODS
Human synovial tissues samples were obtained from RA and osteoarthritis (OA) patients. Disease activity of RA patients was calculated using the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP). The histological features of RA synovial tissues were evaluated using Rooney's inflammation scoring system. The localization of Sema3A, VEGF 165 and NRP1 positive cells was immunohistochemically determined in synovial tissues. Expression levels of Sema3A, VEGF-A and NRP1 mRNA were determined using quantitative real-time polymerase chain reaction (qPCR).


RESULTS
In OA specimens, Sema3A, VEGF 165 and NRP1 proteins were expressed in the synovial lining and inflammatory cells beneath the lining. Immunohistochemistry revealed the protein expression of Sema3A in synovial lining cells was decreased in RA tissues compared with OA samples. qPCR analysis demonstrated a significant reduction of Sema3A mRNA levels in RA synovial tissue samples than in OA and a significant correlation of the ratio of Sema3A/VEGF-A mRNA expression levels with DAS28-CRP (R = -0.449, p = 0.013). Sema3A mRNA levels also correlated with Rooney's inflammation score, especially in perivascular infiltrates of lymphocytes (R = -0.506, p = 0.004), focal aggregates of lymphocytes (R = -0.501, p = 0.005) and diffuse infiltrates of lymphocytes (R = -0.536, p = 0.002).


CONCLUSIONS
Reduction of Sema3A expression in RA synovial tissues may contribute to pathogenesis of RA.
Department of Orthopaedic Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Shu
S
Takagawa
Fumio
F
Nakamura
Ken
K
Kumagai
Yoji
Y
Nagashima
Yoshio
Y
Goshima
Tomoyuki
T
Saito
D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007719:Knee Joint / Q000737:chemistry* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D039942:Neuropilin-1 / Q000032:analysis; D020370:Osteoarthritis, Knee / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A / Q000032:analysis* / Q000235:genetics; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000737:chemistry* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D015415:Biomarkers; D012333:RNA, Messenger; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1