Bone-resorbing osteoclasts are of hemopoietic cell origin, probably of the CFU-M-derived monocytemacrophage family (1). Osteoclasts are large multinucleated giant cells that express tartrate-resistant acid phosphatase (TRAP) activity and calcitonin receptors and have the ability to form resorption pits on dentine slices (2-4). In the process of osteoclast differentiation, there is an absolute requirement for cell-cell contact between osteoclast progenitors and bone marrow stromal cells or calvaria-derived osteoblasts (5-8).We developed a mouse coculture system of hemopoietic cells and primary osteoblasts to investigate osteoclast formation in vitro. In this coculture system, several systemic and local factors were capable of inducing osteoclast-like multinucleated cell (OCL) formation (6-9). These boneresorbing factors were classified into 3 categories according to their signal transduction pathways: (a) 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] induced OCL formation via 1α,25(OH) 2 D 3 receptors (VDR) present in the nuclei; (b) parathyroid hormone (PTH), PTH-related protein (PTHrP), prostaglandin E 2 (PGE 2 ), and IL-1 induced OCL formation via the A kinase system; and (c) IL-11, oncostatin M, leukemia inhibitory factor, and IL-6 in the presence of soluble IL-6 receptors, all of which transduce their signals through a signal-transducing gp130 protein, also induced OCL formation in vitro. We reported previously that the target cells of IL-6 are osteoblasts/stromal cells but that they are not osteoclast precursors in inducing osteoclast differentiation (10). Similarly, coculture experiments using VDR knockout mice and PTH/PTHrP receptor knockout mice have indicated that the signals mediated by 1α,25(OH) 2 D 3 and PTH, respectively, are also transduced into osteoblasts/stromal cells, but not into osteoclast precursors, to induce osteoclast formation (11,12). Thus, it is concluded that the signals induced by all bone-resorbing factors are transduced into osteo-blasts/stromal cells to induce osteoclast formation. Our hypothesis proposes that osteoblasts/stromal cells express a critical common mediator named osteoclast differentiation factor (ODF), a membrane-bound factor that promotes differentiation of osteoclast progenitors into osteoclasts in response to various bone-resorbing factors through a mechanism involving cell-cell contact (6, 8). IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 incre...

Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteoblast action from osteoclast formation, for example, by inhibiting sclerostin, an inhibitor of bone formation that does not influence osteoclast differentiation. Here, we report that oncostatin M (OSM) is produced by osteoblasts and osteocytes in mouse bone and that it has distinct effects when acting through 2 different receptors, OSM receptor (OSMR) and leukemia inhibitory factor receptor (LIFR). Specifically, mouse OSM (mOSM) inhibited sclerostin production in a stromal cell line and in primary murine osteoblast cultures by acting through LIFR. In contrast, when acting through OSMR, mOSM stimulated RANKL production and osteoclast formation. A key role for OSMR in bone turnover was confirmed by the osteopetrotic phenotype of mice lacking OSMR. Furthermore, in contrast to the accepted model, in which mOSM acts only through OSMR, mOSM inhibited sclerostin expression in Osmr -/-osteoblasts and enhanced bone formation in vivo. These data reveal what we believe to be a novel pathway by which bone formation can be stimulated independently of bone resorption and provide new insights into OSMR and LIFR signaling that are relevant to other medical conditions, including cardiovascular and neurodegenerative diseases and cancer.

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