Secreted frizzled-related protein 5 suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes through down-regulation of c-Jun N-terminal kinase.
OBJECTIVE
This study was performed to investigate the effect of secreted frizzled-related protein 5 (Sfrp5), a novel anti-inflammatory adipokine that competes with the frizzled proteins for Wnt binding, on inflammatory response and the c-Jun N-terminal kinase (JNK) signalling pathway in RA.


METHODS
Expression of Sfrp5 mRNA in peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLSs) from patients with RA and OA was determined using real-time quantitative PCR (qPCR). Sfrp5 RNA interference (RNAi) plasmids were transfected to abrogate Sfrp5 expression in RA FLSs, and adenovirus containing the Sfrp5 transcript was delivered into RA FLSs to strengthen Sfrp5 expression. Levels of pro-inflammatory genes and their protein products were determined using real-time qPCR and ELISA in RA FLSs. Production of mitogen-activated protein kinase kinase 7 (MKK-7), JNK and c-Jun were assessed by Western blot analysis.


RESULTS
Expression of Sfrp5 mRNA was decreased in PMBCs and FLSs from patients with RA compared with patients with OA. Gene expression and production of IL-1β, IL-6, chemokine ligand 2 (CCL-2), CCL-7, cyclooxygenase 2 and MMP-9 were markedly increased in Sfrp5 RNAi plasmid-transfected RA FLSs, while transfection with adenoviral vectors encoding Sfrp5 induced reductions in those levels. Phosphorylated forms of MKK-7, JNK and c-Jun were increased by Sfrp5 RNAi plasmids and were decreased by adenoviral vectors encoding Sfrp5.


CONCLUSIONS
Sfrp5 suppressed the inflammatory response and down-regulated JNK signalling in RA FLSs. These findings provide evidence for the anti-inflammatory effect of Sfrp5 in RA.
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Yong-Jin
YJ
Kwon
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Sang-Won
SW
Lee
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Yong-Beom
YB
Park
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Soo-Kon
SK
Lee
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. mcpark@yuhs.ac.
Min-Chan
MC
Park
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D005136:Eye Proteins; D018836:Inflammation Mediators; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D012333:RNA, Messenger; C118511:SFRP5 protein, human; D000094742:Secreted Frizzled-Related Proteins
Wnt signalling; c-Jun N-terminal kinase; fibroblast-like synoviocytes; rheumatoid arthritis; secreted frizzled-related protein 5