Beneficial effect of galectin 9 on rheumatoid arthritis by induction of apoptosis of synovial fibroblasts

• Published in: Arthritis and rheumatism Vol. 56; no. 12; pp. 3968 - 3976
• Main Authors: Seki, Masako, Sakata, Ken‐Mei, Oomizu, Souichi, Arikawa, Tomohiro, Sakata, Atsuko, Ueno, Masaki, Nobumoto, Atsuya, Niki, Toshiro, Saita, Naoki, Ito, Kanako, Dai, Shu‐Yan, Katoh, Shigeki, Nishi, Nozomu, Tsukano, Michishi, Ishikawa, Kouichiro, Yamauchi, Akira, Kuchroo, Vijay, Hirashima, Mitsuomi
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2007; Wiley
• Subjects: Aged; Animals; Apoptosis - physiology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Cell Proliferation; Cells, Cultured; Collagen; Disease Models, Animal; Diseases of the osteoarticular system; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Galectins - metabolism; Hepatitis A Virus Cellular Receptor 2; Humans; Inflammatory joint diseases; Male; Medical sciences; Membrane Proteins - metabolism; Mice; Mice, SCID; Middle Aged; Miscellaneous. Osteoarticular involvement in other diseases; Osteoarthritis; Osteoarthritis - metabolism; Osteoarthritis - pathology; Synovial Fluid - metabolism; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Synovial Membrane - pathology; Human; Immunohistochemistry; Immunopathology; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease; Joint; Anatomic pathology; Chronic; Treatment; Synovial membrane; Animal; Rheumatoid arthritis; Arthropathy; Degenerative disease; Bone; Osteoarthritis; Fibroblast; Apoptosis
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.23076

Objective To compare the expression of galectin 9 (Gal‐9) in synovial tissue (ST) from rheumatoid arthritis (RA) patients and osteoarthritis (OA) patients and to evaluate the effects of Gal‐9 on fibroblast‐like synoviocytes (FLS) in these patients. Methods The expression of Gal‐9 in ST and FLS was compared using immunohistochemical techniques. Apoptotic cells in RA and OA ST samples were detected by TUNEL assay. Apoptosis of FLS was analyzed by the sub‐G1 method in vitro. The in vivo suppressive effects of Gal‐9 on collagen‐induced arthritis (CIA) in a mouse model were also elucidated. Results The percentage of Gal‐9–positive cells in ST samples and the amount of Gal‐9 in synovial fluid samples were significantly higher in patients with RA than in patients with OA, suggesting the involvement of Gal‐9 in the development of RA. Compared with the 2 wild‐type Gal‐9 forms, stable Gal‐9, a mutant protein resistant to proteolysis, significantly induced apoptosis of FLS from RA patients. In contrast, other galectins, such as Gal‐1, Gal‐3, and Gal‐8, did not induce apoptosis or suppress the proliferation of human RA FLS. Stable Gal‐9 preferentially induced apoptosis and suppressed the proliferation of RA FLS in vitro. It also induced apoptosis of cells in RA ST implanted into SCID mice in vivo. In a mouse model of CIA, apoptotic cells were detected in the joints of stable Gal‐9–treated mice, but not phosphate buffered saline–treated mice, and suppressed CIA characterized by pannus formation with inflammatory cell infiltration and bone/cartilage destruction. Conclusion Gal‐9–induced apoptosis of hyperproliferative RA FLS may play a critical role in the suppression of RA.