Fibulin-4 is a target of autoimmunity predominantly in patients with osteoarthritis.
Autoimmunity to chondrocyte-producing proteins has been reported in patients with osteoarthritis (OA) as well as in those with rheumatoid arthritis (RA). To answer whether or not OA-specific autoimmunity exist, we performed screening of chondrocyte-producing autoantigens by two-dimensional electrophoresis and Western blotting with each of 20 OA and 20 RA serum samples. We identified an apparently OA-specific autoantigen spot with a molecular mass of 52 kDa and a Isoelectric point of 4.1 as fibulin-4 by mass fingerprinting. By preparing recombinant proteins of fibulin-4, we determined prevalence of the autoantibodies to fibulin-4 in 92 patients with OA, 67 patients with RA, 40 patients with systemic lupus erythematosus, and 43 patients with systemic scleroderma. As a result, the IgG type anti-fibulin-4 autoantibodies were detected in 23.9% of sera from patients with OA, in 8.9% of sera from patients with RA, in 2.5% of sera from patients with systemic lupus erythematosus, and in 9.3% of sera from patients with systemic scleroderma. Furthermore, we immunized DBA/1J, ICR, BALB/c, and C57BL/6 mice with the recombinant fibulin-4 proteins to investigate arthritogenecity of fibulin-4. As a result, mild synovitis was detected in all of the four strains. In addition, we demonstrated expression of fibulin-4 in chondrocytes at both mRNA and protein levels in vivo and in vitro by RT-PCR, Western blotting, and immunohistochemistry. Taken together, fibulin-4, expressed in chondrocytes and recognized as an autoantigen mainly in OA rather than in RA, may play pathogenic roles in OA.
Department of Bioregulation and Proteomics, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Yang
Y
Xiang
Taichi
T
Sekine
Hiroshi
H
Nakamura
Shinobu
S
Imajoh-Ohmi
Hiroyuki
H
Fukuda
Kazuo
K
Yudoh
Kayo
K
Masuko-Hongo
Kusuki
K
Nishioka
Tomohiro
T
Kato
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001324:Autoantigens / Q000008:administration & dosage / Q000096:biosynthesis*; D019902:Chondrocytes / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D008875:Middle Aged; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology; D010003:Osteoarthritis / Q000097:blood / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D012595:Scleroderma, Systemic / Q000276:immunology; D013585:Synovitis / Q000276:immunology
D001324:Autoantigens; C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D007074:Immunoglobulin G; D004676:Myelin Basic Protein; D011993:Recombinant Fusion Proteins