This study investigates the role of soluble interleukin-6 receptor (sIL-6R) in osteoclast formation induced by interleukin 6 (IL-6). The authors found that neither recombinant mouse IL-6 nor mouse sIL-6R alone induced osteoclast-like multinucleated cell (MNC) formation in a coculture system of mouse osteoblasts and bone marrow cells. However, simultaneous treatment with both IL-6 and sIL-6R significantly induced MNC formation, which 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 was dose-dependently inhibited by adding monoclonal anti-mouse IL-6R antibody (MR16-1). Additionally, factors like IL-11, oncostatin M, and leukemia inhibitory factor, which transduce signals through gp130, also induced MNC formation. These results suggest that increased circulating or locally produced sIL-6R can induce osteoclast formation in the presence of IL-6 through a mechanism involving gp130, potentially playing a significant role in conditions associated with increased osteoclastic bone resorption.This study investigates the role of soluble interleukin-6 receptor (sIL-6R) in osteoclast formation induced by interleukin 6 (IL-6). The authors found that neither recombinant mouse IL-6 nor mouse sIL-6R alone induced osteoclast-like multinucleated cell (MNC) formation in a coculture system of mouse osteoblasts and bone marrow cells. However, simultaneous treatment with both IL-6 and sIL-6R significantly induced MNC formation, which 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 was dose-dependently inhibited by adding monoclonal anti-mouse IL-6R antibody (MR16-1). Additionally, factors like IL-11, oncostatin M, and leukemia inhibitory factor, which transduce signals through gp130, also induced MNC formation. These results suggest that increased circulating or locally produced sIL-6R can induce osteoclast formation in the presence of IL-6 through a mechanism involving gp130, potentially playing a significant role in conditions associated with increased osteoclastic bone resorption.