Early effects of tocilizumab on bone and bone marrow lesions in a collagen-induced arthritis monkey model

• Published in: Experimental and molecular pathology 2008-06, Vol.84 (3), p.262-270
• Main Authors: Kato, Atsuhiko, Matsuo, Saori, Takai, Hirotake, Uchiyama, Yasushi, Mihara, Masahiko, Suzuki, Masami
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow - immunology; Bone Marrow - pathology; Collagen-induced arthritis model; Diseases of the osteoarticular system; Female; IL-6; IL-6R; Inflammatory joint diseases; Interleukin-6 - physiology; Investigative techniques, diagnostic techniques (general aspects); Macaca fascicularis; Medical sciences; Osteoblast/stromal cells; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - immunology; Osteoclasts - pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; RANK; RANK Ligand - metabolism; RANKL; Receptor Activator of Nuclear Factor-kappa B - metabolism; Receptors, Interleukin-6 - physiology; Reticulum fibers; Rheumatoid arthritis; Tocilizumab
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2008.03.003

To understand the contribution of IL-6/IL-6R to subchondral bone and bone marrow abnormality in RA patients and the effects of tocilizumab on those abnormalities, we evaluated early change in a collagen-induced arthritis (CIA) monkey model with or without a single administration of tocilizumab. Six CIA cynomolgus monkeys received tocilizumab and 3 CIA monkeys received vehicle only. Their interphalangeal joints were analyzed using HE, silver impregnation (SI), or immunohistochemistry (RANKL) staining. The number of osteoclasts increased in the arthritis control but was suppressed in the tocilizumab-treated animals. Osteoblast/stromal cells of the arthritis control monkeys were of monolayer, while in the tocilizumab-treated monkeys, the cells were multi-layer or differentiated osteoblasts, and the meshwork of the reticulum fibers showed recovery in the SI. Hematopoietic marrow was replaced by interstitial fluid and reticulum fibers were eliminated in the arthritic model but showed recovery in the tocilizumab-treated animals. RANKL showed overproduction with arthritis and suppressed with tocilizumab treatment. The evidence indicates that IL-6/IL-6R is involved in subchondral bone and bone marrow change in RA patients. Tocilizumab treatment recovered changes in the CIA monkeys as a result of the co-differentiation between the osteoclasts and the osteoblast/stramal cells, at least partially through the suppression of RANKL overproduction.