Oncostatin M, an Inflammatory Cytokine Produced by Macrophages, Supports Intramembranous Bone Healing in a Mouse Model of Tibia Injury.

American Journal of Pathology

PubMedID: 25559270

Guihard P, Boutet M, Brounais-Le Royer B, Gamblin A, Amiaud J, Renaud A, Berreur M, Rédini F, Heymann D, Layrolle P, Blanchard F. Oncostatin M, an Inflammatory Cytokine Produced by Macrophages, Supports Intramembranous Bone Healing in a Mouse Model of Tibia Injury. Am J Pathol. 2015;185(3):765-75.
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) was overexpressed during the initial inflammatory phase and that depletion of macrophages repressed OSM 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 OSM, 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 OSM receptor (Osmr(-/-)) also had reduced bone formation and osteoblast number within the injury site. These results suggest that OSM, 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.