title: Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass.
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)-gp130 heterodimer and binds with only very low affinity to mLIFR. hOSM and mLIF stimulate bone remodeling by both reducing osteocytic sclerostin and up-regulating the pro-osteoclastic factor receptor activator of NF-κB ligand (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 signaling activated by the low affinity interaction of mOSM with mLIFR is different from the downstream effects when mLIF or hOSM interacts with the same receptor. Both STAT1 and STAT3 were activated by mOSM in wild type cells or by mLIF/hOSM in wild type and Osmr-/-cells. In contrast, in Osmr-/-primary osteocyte-like cells stimulated with mOSM (therefore acting through mLIFR), microarray expression profiling and Western blotting 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 signaling downstream of gp130 (gp130Y757F/Y757F), STAT1 deletion rescued the osteopenic phenotype, indicating a beneficial effect of promoting STAT3 signaling over STAT1 downstream of gp130 in this low bone mass condition, and this may have therapeutic value.
authors.affiliation: From the St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Walker
authors.affiliation: From the St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Rachelle W
authors.initials: RW
authors.lastname: Johnson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: From the St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Brennan
authors.affiliation: From the St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Poulton
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Medical Biology, and.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton 3168, Victoria, Australia, and.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Departments of Mathematics and Statistics.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Medical Biology, and.
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.affiliation: From the St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia, nsims@svi.edu.au.|Medicine at St. Vincent's Hospital, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053683:Oncostatin M / Q000235:genetics / Q000378:metabolism*; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C494200:Il6st protein, mouse; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D053681:Oncostatin M Receptor beta Subunit; C508349:Osmr protein, mouse; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D053683:Oncostatin M; D050822:Cytokine Receptor gp130
keywords: STAT3; cytokine; glycoprotein 130; leukemia inhibitory factor; oncostatin M; osteoblast; osteocyte; signal transducers and activators of transcription 1 (STAT1)