title: Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling.
abstract: Bone resorption by osteoclasts and bone formation by osteoblasts are tightly coupled processes implicating factors in TNF, bone morphogenetic protein, and Wnt families. In osteoimmunology, macrophages were described as another critical cell population regulating bone formation by osteoblasts but the coupling factors were not identified. Using a high-throughput approach, we identified here Oncostatin M (OSM), a cytokine of the IL-6 family, as a major coupling factor produced by activated circulating CD14+ or bone marrow CD11b+ monocytes/macrophages that induce osteoblast differentiation and matrix mineralization from human mesenchymal stem cells while inhibiting adipogenesis. Upon activation of toll-like receptors (TLRs) by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated inflammatory M1 and not M2 macrophages, through a cyclooxygenase-2 and prostaglandin-E2 regulatory loop. Stimulation of osteogenesis by activated monocytes/macrophages was prevented using neutralizing antibodies or siRNA to OSM, OSM receptor subunits gp130 and OSMR, or to the downstream transcription factor STAT3. The induced osteoblast differentiation program culminated with enhanced expression of CCAAT-enhancer-binding protein δ, Cbfa1, and alkaline phosphatase. Overexpression of OSM in the tibia of mice has led to new bone apposition with no sign of bone resorption. Two other cytokines have also a potent role in bone formation induced by monocytes/macrophages and activation of TLRs: IL-6 and leukemia inhibitory factor. We propose that during bone inflammation, infection, or injury, the IL-6 family signaling network activated by macrophages and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus an important target for anabolic bone therapies.
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Guihard
authors.forename: Yannic
authors.initials: Y
authors.lastname: Danger
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Brounais
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: David
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.forename: Joël
authors.initials: J
authors.lastname: Delecrin
authors.forename: Carl D
authors.initials: CD
authors.lastname: Richards
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevalier
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Hugues
authors.initials: H
authors.lastname: Gascan
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanchard
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053683:Oncostatin M / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008070:Lipopolysaccharides; D053683:Oncostatin M; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone