Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice
Emma C. Walker, … , T. John Martin, Natalie A. Sims
Emma C. Walker, … , T. John Martin, Natalie A. Sims
Published January 4, 2010
Citation Information: J Clin Invest. 2010;120(2):582-592. https://doi.org/10.1172/JCI40568.
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Research Article Bone biology

Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice

Abstract

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.

Authors

Emma C. Walker, Narelle E. McGregor, Ingrid J. Poulton, Melissa Solano, Sueli Pompolo, Tania J. Fernandes, Matthew J. Constable, Geoff C. Nicholson, Jian-Guo Zhang, Nicos A. Nicola, Matthew T. Gillespie, T. John Martin, Natalie A. Sims

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Figure 5

OSMR expression by osteoblasts is required for normal osteoclast and osteoblast activity; sclerostin is regulated by mOSM in Osmr–/– mice.

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OSMR expression by osteoblasts is required for normal osteoclast and ost...
(A) Tartrate-resistant acid phosphatase–positive multinucleated osteoclast-like cell (TRAP+ MNC) formation in response to RANKL from Osmr–/– BM macrophages compared with WT BM. In the presence of Osmr–/– osteoblasts, osteoclast formation from either Osmr–/– or WT BM in response to mOSM was completely blocked, and osteoclast formation in response to PGE2 and 1,25D3 (PGE2/D3) was inhibited. (B) Rankl mRNA was increased by mOSM treatment in WT calvarial osteoblasts, but not in Osmr–/– calvarial osteoblasts. Rankl mRNA levels were also significantly increased by PGE2/D3 in both WT and Osmr–/– primary calvarial osteoblasts 8 hours after treatment was commenced. (C and D) Mineralization, measured by alizarin red staining after 21 days of culture in mineralizing medium, and ALP activity in cells grown in osteoblast differentiation medium were both significantly reduced in calvarial osteoblasts generated from Osmr–/– mice compared with WT littermates. (E–H) Cebpb, Cebpd, Pparg, and Sost mRNA levels, relative to HPRT1 in WT and Osmr–/– calvarial osteoblasts after treatment with 10 ng/ml mOSM. PPARγ and SOST are measured in cells differentiated for 17 days in osteoblast differentiation medium. All data in Figure 5 are shown as mean + SEM from 3–4 independent experiments, carried out in triplicate. *P < 0.05; **P < 0.01; ***P < 0.001 vs. untreated control at the same time point.