title: Oncostatin M induces bone loss and sensitizes rat osteosarcoma to the antitumor effect of Midostaurin in vivo.
abstract: OBJECTIVE
  In cultures, the cytokine oncostatin M (OSM) reduces the growth and induces differentiation of osteoblasts and osteosarcoma cells into glial/osteocytic cells. Moreover, OSM sensitizes these cells to apoptosis driven by various death inducers such as the kinase inhibitor staurosporine. Here, we asked whether OSM would have similar effects in vivo.
  
  
  METHODS
  Adenoviral gene transfer of OSM (AdOSM) was done in naive and osteosarcoma-bearing rats, alone or in combination with Midostaurin (PKC412), a derivative of staurosporine currently used in cancer clinical trials. Bone variables were analyzed by micro-computed tomography scanner, by histology, and by the levels of various serum bone markers. Osteosarcoma progression was analyzed by the development of the primary bone tumor, evolution of pulmonary metastasis, histology (necrosis and fibrosis), and animal survival.
  
  
  RESULTS
  In naive rats, AdOSM reduced serum osteoblastic and osteoclastic markers in correlation with a reduced trabecular bone volume. In an osteosarcoma rat model, the combination of AdOSM with PKC412 reduced the progression of the primary bone tumor, pulmonary metastatic dissemination, and increased overall survival, whereas these agents alone had no antitumor effect. Increased tumor necrosis and tissue repair (fibrosis) were observed with this combination.
  
  
  CONCLUSIONS
  These in vivo experiments confirm that systemic OSM overexpression alters osteoblast/osteosarcoma activity. Because OSM sensitizes rat osteosarcoma to apoptosis/necrosis, the use of kinase inhibitors such as Midostaurin in association with OSM could represent new adjuvant treatments for this aggressive malignancy.
authors.affiliation: INSERM, ERI 7, Nantes, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Brounais
authors.forename: Céline
authors.initials: C
authors.lastname: Chipoy
authors.forename: Kanji
authors.initials: K
authors.lastname: Mori
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.forename: Séverine
authors.initials: S
authors.lastname: Battaglia
authors.forename: Paul
authors.initials: P
authors.lastname: Pilet
authors.forename: Carl D
authors.initials: CD
authors.lastname: Richards
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanchard