Abstract
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. 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. 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. 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.
Highlights
In cultures, the cytokine oncostatin M (OSM) reduces the growth and induces differentiation of osteoblasts and osteosarcoma cells into glial/osteocytic cells
It is possible that these dual effects depend on the differentiation stage of the osteoblast or osteosarcoma cells: on precursor cells, OSM would stimulate the first stages of differentiation, but on more mature cells it would stimulate the terminal differentiation into osteocytes characterized by reduced marker expression/ bone formation/proliferation and enhanced apoptosis [15]
We recently described that OSM inhibits proliferation and sensitizes rat OSRGA osteosarcoma cells to apoptosis driven by various death inducers such as STS, UV, or tumor necrosis factor-a [15, 17]
Summary
The cytokine oncostatin M (OSM) reduces the growth and induces differentiation of osteoblasts and osteosarcoma cells into glial/osteocytic cells. 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. It is possible that these dual effects depend on the differentiation stage of the osteoblast or osteosarcoma cells: on precursor cells, OSM would stimulate the first stages of differentiation, but on more mature cells it would stimulate the terminal differentiation into osteocytes characterized by reduced marker expression/ bone formation/proliferation and enhanced apoptosis [15]. We observed that OSM alone does not induce cell death, but wild-type p53 osteoblastic or osteosarcoma cells treated with OSM are sensitive to apoptosis induced by staurosporine (STS), UV, or tumor necrosis factor-a [17]. OSM, through activation of STAT5 and p53, increases the Bax/Bcl ratio, which controls the mitochondrial apoptotic pathway, but concomitantly activates antiapoptotic signals through the kinases protein kinase Cy and phosphatidylinostiol 3-kinase/Akt [17]
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