Regenerating gene (REG) 1 alpha promotes pannus progression in patients with rheumatoid arthritis.
BACKGROUND
A protein analysis using mass spectrometry revealed the existence of serum proteins with significant quantitative changes after the administration of infliximab. Among these proteins, regenerating gene (REG) 1α appears to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, the present study was conducted to examine the mechanism of REG1α in RA disease progression.


METHODS
Serum samples were collected from RA patients and normal healthy controls. REG1α expression was evaluated by ELISA, RT-PCR, and indirect immunofluorescence microscopy. The functions of REG1α on synovial fibroblasts with regard to apoptosis, receptor activator of NF-κB ligand (RANKL) expression, and cellar proliferation were evaluated using siRNA to inhibit the intrinsic REG1α mRNA expression.


RESULTS
The serum concentrations of REG1α in RA patients were higher than in normal healthy controls. The high expression of REG1α was also observed in the synovial tissue of RA patients compared to those of osteoarthropathy patients. In addition, tumor necrosis factor-α (TNF-α) upregulated REG1α expression in the synovial fibroblasts cell line (MH7A). Inhibition of REG1α expression suppressed the induction of RANKL expression by TNF-α. Furthermore, exogenous recombinant REG1α protein inhibited apoptosis and promoted cell proliferation in MH7A cells. These effects were abolished in the REG1α-siRNA MH7A cells.


CONCLUSIONS
The present data suggest that TNF-α induces aberrant REG1α expression and that REG1α plays an important role in aberrant cell proliferation and RANKL expression of synovial fibroblasts, ultimately resulting in pannus formation. Restoration of normal physiological REG1α expression may contribute to disease amelioration.
Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan, mfujishi@juntendo.ac.jp
Maki
M
Fujishiro
Kazuhisa
K
Nozawa
Mikiko
M
Kawasaki
Ayako
A
Yamaguchi
Kazuhisa
K
Iwabuchi
Mitsuaki
M
Yanagida
Fujihiko
F
Suzuki
Keiji
K
Miyazawa
Hirokazu
H
Fukui
Kazuo
K
Kaneko
Hideoki
H
Ogawa
Kenji
K
Takamori
Yoshinari
Y
Takasaki
Iwao
I
Sekigawa
D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020868:Gene Silencing; D006097:Granulation Tissue / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051847:Lithostathine / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051847:Lithostathine; D053245:RANK Ligand; C497617:REG1A protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha