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.

Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration

“…In mouse cells, OSM has long been thought to signal only through OSMR/gp130 [33]. However, this view was recently challenged [34]. We provide evidence here showing that OSM potently inhibits myoblast differentiation by selectively activating the JAK1/STAT1/STAT3 pathway.…”

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

“…For microarray validation experiments, Kusa 4b10 were serum starved (2% FBS) on day 16 of differentiation for 18 h prior to treatment with the indicated doses of PTH(1-34) (10 nM), and mouse CT-1 or mouse OSM (50 ng/ml; R&D Systems) for the times indicated. Mouse primary osteoblasts were prepared by enzymatic digestion of calvariae of newborn wild-type (WT) C57BL/6 mice (1-2 days old) (20,21). Mineralized nodules were stained by von Kossa with 3% silver nitrate and fixation with 0.1% sodium thiosulfate.…”

“…The gp130-signaling cytokines OSM and CT-1 have been reported to have similar effects on bone formation to PTH in that they stimulate osteoblast differentiation and inhibit adipogenesis (20,21). Mice null for OSM receptor or CT-1 demonstrated impaired bone formation and high marrow adiposity (20,21).…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…(85) In mice, oncostatin M, a cytokine expressed by osteoblasts, osteocytes, and activated T cells, has been found to downregulate sclerostin expression by signaling through the leukemia inhibitory factor receptor (LIFR)-gp130 receptor complex. (86) In a mouse model of chronic colitis, short-term treatment with Scl-Ab had no anti-inflammatory effects but increased bone formation and reversed both inflammationinduced bone loss and the inflammation-induced decline in bone mechanical properties. (87) Circulating TRACP5b levels were decreased, suggesting that administration of Scl-Ab also reduced osteoclast-mediated bone resorption.…”