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      Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6.

      Proceedings of the National Academy of Sciences of the United States of America
      Animals, Antibodies, Monoclonal, Bone Marrow Cells, CHO Cells, Cells, Cultured, Cricetinae, Female, HIV Infections, blood, immunology, Humans, Interleukin-6, pharmacology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred Strains, Mice, Nude, Multiple Myeloma, Osteoclasts, cytology, drug effects, physiology, Rats, Rats, Wistar, Receptors, Interleukin, metabolism, Receptors, Interleukin-6, Recombinant Proteins, Transfection

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          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.

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