title: Oncostatin m, an inflammatory cytokine produced by macrophages, supports intramembranous bone healing in a mouse model of tibia injury.
abstract: Different macrophage depletion strategies have demonstrated a vital role of macrophages in bone healing, but the underlying molecular mechanisms are poorly understood. Here, with the use of a mouse model of tibia injury, we found that the cytokine oncostatin M [OSM or murine (m)OSM] was overexpressed during the initial inflammatory phase and that depletion of macrophages repressed mOSM expression. In Osm(-/-) mice, by micro-computed tomography and histology we observed a significant reduction in the amount of new intramedullar woven bone formed at the injured site, reduced number of Osterix(+) osteoblastic cells, and reduced expression of the osteoblast markers runt-related transcription factor 2 and alkaline phosphatase. In contrast, osteoclasts were normal throughout the healing period. One day after bone injury, Stat3, the main transcription factor activated by mOSM, was found phosphorylated/activated in endosteal osteoblastic cells located at the hedge of the hematoma. Interestingly, we observed reduced activation of Stat3 in Osm(-/-) mice. In addition, mice deficient in the mOSM receptor (Osmr(-/-)) also had reduced bone formation and osteoblast number within the injury site. These results suggest that mOSM, a product of macrophages, sustains intramembranous bone formation by signaling through Osmr and Stat3, acting on the recruitment, proliferation, and/or osteoblast differentiation of endosteal mesenchymal progenitor cells. Because bone resorption is largely unaltered, OSM could represent a new anabolic treatment for unconsolidated bone fractures.
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Guihard
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Boutet
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Brounais-Le Royer
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Gamblin
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Renaud
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Berreur
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Layrolle
authors.affiliation: INSERM, UMR 957, Ligue Team 2012, Nantes, France; Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumors, Medicine Faculty, Université de Nantes, Nantes Atlantique Universités, Nantes, France. Electronic address: frederic.blanchard@univ-nantes.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanchard
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D053683:Oncostatin M / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis; D053677:Receptors, Oncostatin M / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013977:Tibia / Q000293:injuries* / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D053677:Receptors, Oncostatin M; C493716:Runx2 protein, mouse; D050796:STAT3 Transcription Factor; D053683:Oncostatin M; D000469:Alkaline Phosphatase