Rheumatoid arthritis fibroblast-like synoviocytes express BCMA and are stimulated by APRIL.
OBJECTIVE
Fibroblast-like synoviocytes (FLS) are among the principal effector cells in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to examine the variety of stimulating effects of APRIL and its specific effect on FLS in the affected RA synovium.


METHODS
Synovium and serum samples were obtained from patients with RA, patients with osteoarthritis (OA), and healthy subjects. Soluble APRIL proteins were assayed by enzyme-linked immunosorbent assay. The relative gene expression of APRIL, BCMA, interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), IL-1beta, and RANKL was assessed in RA and OA FLS by polymerase chain reaction. Effects of APRIL on the production of proinflammatory cytokines and RANKL in RA FLS were investigated by flow cytometry and with the use of a BCMA-Fc fusion protein.


RESULTS
A significantly higher level of soluble APRIL was detected in RA serum compared with normal serum. Among the 3 receptors of APRIL tested, RA FLS expressed only BCMA, whereas OA FLS expressed none of the receptors. APRIL stimulated RA FLS, but not OA FLS, to produce IL-6, TNFalpha, IL-1beta, and APRIL itself. In addition, APRIL increased RA FLS expression of RANKL and also enhanced progression of the cell cycle of RA FLS. Neutralization of APRIL by the BCMA-Fc fusion protein attenuated all of these stimulating effects of APRIL on RA FLS.


CONCLUSIONS
RA FLS are stimulated by APRIL and express the APRIL receptor BCMA. These results provide evidence that APRIL is one of the main regulators in the pathogenesis of RA.
Nagatani
Katsuya
K
International Medical Center of Japan, Shinjuku, Tokyo, Japan.
Itoh
Kenji
K
Nakajima
Kyoichi
K
Kuroki
Hirohumi
H
Katsuragawa
Yozo
Y
Mochizuki
Makoto
M
Aotsuka
Shinichi
S
Mimori
Akio
A
D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D005260:Female; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000473:pathology* / Q000502:physiology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000097:blood / Q000235:genetics*
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D016207:Cytokines; D053245:RANK Ligand; C435926:TNFRSF13C protein, human; C086966:TNFRSF17 protein, human; C505688:TNFSF11 protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13