Soluble Interleukin-6 Receptor Triggers Osteoclast Formation by Interleukin 6

• Published in: Proceedings of the National Academy of Sciences - PNAS 1993-12, Vol.90 (24), p.11924-11928
• Main Authors: Tamura, Tatsuya, Udagawa, Nobuyuki, Takahashi, Naoyuki, Miyaura, Chisato, Tanaka, Sakae, Yamada, Yoshiki, Koishihara, Yasuo, Ohsugi, Yoshiyuki, Kumaki, Kenji, Taga, Tetsuya, Kishimoto, Tadamitsu, Suda, Tatsuo
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Analytical, structural and metabolic biochemistry; Animals; Antibodies; Antibodies, Monoclonal; Biochemistry; Biological and medical sciences; Bone marrow; Bone Marrow Cells; Bone resorption; Bones; Cells, Cultured; Cellular biology; CHO Cells; Coculture techniques; Cricetinae; Cytokines; Female; Fundamental and applied biological sciences. Psychology; HIV Infections - blood; HIV Infections - immunology; Humans; Interleukin-6 - pharmacology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mice, Nude; Multiple Myeloma - blood; Multiple Myeloma - immunology; Osteoclasts; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - physiology; Protein hormones. Growth factors. Cytokines; Proteins; Rats; Rats, Wistar; Receptors; Receptors, Interleukin - metabolism; Receptors, Interleukin-6; Recombinant Proteins - pharmacology; Rodents; Spleen cells; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.24.11924

It has been reported that soluble interleukin (IL)-6 receptor (sIL-6R) is detected in the serum of healthy individuals and its level is increased in patients with multiple myeloma and human immunodeficiency virus infection. Although several reports have suggested that sIL-6R potentiates IL-6 action, its physiological role remains unclear. In this study, we examined the role of sIL-6R on osteoclast formation by IL-6, using a coculture of mouse osteoblasts and bone marrow cells. Neither recombinant mouse IL-6 (mIL-6) nor mouse sIL-6R (smIL-6R) induced osteoclast-like multinucleated cell (MNC) formation when they were added separately. In contrast, simultaneous treatment with mIL-6 and smIL-6R strikingly induced MNC formation. These MNCs satisfied major criteria of authentic osteoclasts, such as tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. The MNC formation induced by mIL-6 and smIL-6R was dose-dependently inhibited by adding monoclonal anti-mouse IL-6R antibody (MR16-1). It is likely that osteoblasts and osteoclast progenitors are capable of transducing a signal from a complex of IL-6 and sIL-6R through gp130, even though they may have no or a very small number of IL-6Rs. Factors such as IL-11, oncostatin M, and leukemia inhibitory factor, which are known to exert their functions through gp130 (the signal-transducing chain of IL-6R), also induced MNC formation in our coculture system. These results suggest that increased circulating or locally produced sIL-6R induces osteoclast formation in the presence of IL-6 mediated by a mechanism involving gp130. This may play an important physiological or pathological role in conditions associated with increased osteoclastic bone resorption.