Murine Oncostatin M acts via Leukemia Inhibitory Factor Receptor to phosphorylate STAT3 but not STAT1, an effect that protects bone mass

Walker, EC; Johnson, RW; Hu, Y; Brennan, HJ; Poulton, IJ; Zhang, JG; Jenkins, BJ; Smyth, GK; Nicola, NA; Sims, NA

Author(s): Walker, EC; Johnson, RW; Hu, Y; Brennan, HJ; Poulton, IJ; Zhang, JG; Jenkins, BJ; Smyth, GK; Nicola, NA; Sims, NA;
Details: Publication Year 2016-08-18,Volume 291,Issue #41,Page 21703-21716
Journal Title: Journal of Biological Chemistry
Publication Type: Journal Article
Abstract: Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are IL-6 family members with a wide range of biological functions. Human OSM (hOSM) and murine LIF (mLIF) act in mouse cells via a LIF receptor (LIFR): glycoprotein 130 (gp130) heterodimer. In contrast, murine OSM (mOSM) signals mainly via an OSM receptor (OSMR):glycoprotein 130 (gp130) heterodimer, and binds with only very low affinity to mLIFR. hOSM and mLIF stimulate bone remodelling both by reducing osteocytic sclerostin and upregulating the pro-osteoclastic factor RANKL in osteoblasts. In the absence of OSMR, mOSM still strongly suppressed sclerostin and stimulated bone formation but did not induce RANKL suggesting that intracellular signalling activated by the low-affinity interaction of mOSM with mLIFR is different to the downstream effects when mLIF or hOSM interact with the same receptor. Both STAT1 and STAT3 were activated by mOSM in wildtype cells or by mLIF/hOSM in wildtype and Osmr-/- cells. In contrast, in Osmr-/- primary osteocyte-like cells stimulated with mOSM (therefore acting through mLIFR), microarray expression profiling and Western blot analysis identified preferential phosphorylation of STAT3 and induction of its target genes but not of STAT1 and its target genes; this correlated with reduced phosphorylation of both gp130 and LIFR. In a mouse model of spontaneous osteopenia caused by hyperactivation of STAT1/3 signalling downstream of gp130 (gp130Y757F/Y757F), STAT1 deletion rescued the osteopenic phenotype, indicating a beneficial effect of promoting STAT3 signalling over STAT1 downstream of gp130 in this low bone mass condition, and this may have therapeutic value.
Publisher: ASBMB
Research Division(s): Cancer And Haematology; Bioinformatics
PubMed ID: 27539849
Publisher's Version: https://doi.org/10.1074/jbc.M116.748483
NHMRC Grants: NHMRC/1004945, NHMRC/1058625, NHMRC/1054618,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-09-06 09:00:26

Last Modified: 2018-07-05 09:20:34