Soluble interleukin-6 receptor (sIL-6R) promotes osteoclast formation through interleukin-6 (IL-6). This study demonstrates that when IL-6 and sIL-6R are simultaneously present, they induce the formation of osteoclast-like multinucleated cells (MNCs) in a coculture system of mouse osteoblasts and bone marrow cells. These MNCs exhibit characteristics of authentic osteoclasts, including tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. The formation of MNCs was dose-dependently inhibited by a monoclonal anti-mouse IL-6R antibody, suggesting that osteoblasts and osteoclast progenitors can transduce signals through the gp130 receptor complex, even in the absence of functional IL-6 receptors. Other cytokines, such as IL-11, oncostatin M, and leukemia inhibitory factor, which also use gp130 for signaling, were found to induce MNC formation in the same coculture system. These findings suggest that increased levels of sIL-6R, either circulating or locally produced, can enhance IL-6-mediated osteoclast formation through the gp130 pathway. This mechanism may play a significant physiological or pathological role in conditions associated with increased osteoclastic bone resorption, such as multiple myeloma, rheumatoid arthritis, and postmenopausal osteoporosis. The study highlights the importance of sIL-6R in IL-6 signaling and its potential role in bone metabolism.Soluble interleukin-6 receptor (sIL-6R) promotes osteoclast formation through interleukin-6 (IL-6). This study demonstrates that when IL-6 and sIL-6R are simultaneously present, they induce the formation of osteoclast-like multinucleated cells (MNCs) in a coculture system of mouse osteoblasts and bone marrow cells. These MNCs exhibit characteristics of authentic osteoclasts, including tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. The formation of MNCs was dose-dependently inhibited by a monoclonal anti-mouse IL-6R antibody, suggesting that osteoblasts and osteoclast progenitors can transduce signals through the gp130 receptor complex, even in the absence of functional IL-6 receptors. Other cytokines, such as IL-11, oncostatin M, and leukemia inhibitory factor, which also use gp130 for signaling, were found to induce MNC formation in the same coculture system. These findings suggest that increased levels of sIL-6R, either circulating or locally produced, can enhance IL-6-mediated osteoclast formation through the gp130 pathway. This mechanism may play a significant physiological or pathological role in conditions associated with increased osteoclastic bone resorption, such as multiple myeloma, rheumatoid arthritis, and postmenopausal osteoporosis. The study highlights the importance of sIL-6R in IL-6 signaling and its potential role in bone metabolism.