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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 Article has an altmetric score of 4

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

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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 6

mOSM stimulates RANKL via OSMR yet inhibits sclerostin via LIFR and stimulates bone formation in Osmr–/– mice.

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mOSM stimulates RANKL via OSMR yet inhibits sclerostin via LIFR and stim...
(A and B) Fold changes in Rankl and Sost mRNA levels in primary calvarial osteoblasts 6 hours after commencing treatment with mLIF, hOSM, or mOSM (all 2 ng/ml) with and without 1 hour pretreatment with 2.5 μg/ml LA. Mean ± SEM of 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001 vs. vehicle-treated cells of the same genotype and antagonist exposure. (C) Phosphorylation of WT and Osmr–/– osteoblasts stimulated with mLIF, hOSM, or mOSM (each 50 ng/ml). pSTAT1/STAT1 (90 kDa), pSTAT3/STAT3 (86 kDa), pSTAT5/STAT5 (90 kDa) detected between 98 kDa and 62 kDa molecular weight markers (left side of figure). pERK/ERK (42/44 kDa) and pan-actin (42 kDa) were detected between 49 kDa and 38 kDa. The pSTAT3/STAT3 Western blot is from 1 film, but it has been spliced to maintain a consistent order within the figure. pSTAT1/STAT1 and pERK/ERK were probed sequentially on the same gel. (D) hOSM and mOSM (both 2 ng/ml) injected over calvariae of Osmr–/– mice (n = 5–6/group) increased calvarial thickness (Cv.Th.) without increasing MS/BS, but increased MAR, and hOSM increased BFR/BS compared with saline-treated controls. *P < 0.05; **P < 0.01, vs. saline-treated control. (E) A model of mOSM action. OSM, produced by osteoblasts, osteocytes, and bone-lining cells acts through OSMR in osteoblasts and their precursors to promote osteoblast differentiation and inhibit adipocyte differentiation as well as stimulating osteoclast differentiation by increasing RANKL expression. In contrast, in the osteocyte, mOSM acts through LIFR in osteocytes to inhibit sclerostin, an osteocyte-specific inhibitor of mineralization, thus modifying bone formation independently of effects on osteoclast and adipocyte differentiation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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