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 1 or bone marrow CD11b 1 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 d, 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. STEM CELLS 2012;30:762-772 Disclosure of potential conflicts of interest is found at the end of this article.

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Oncostatin M (OSM), a cytokine of the interleukin-6 family, induces growth arrest and differentiation of osteoblastic cells into glial-like/osteocytic cells. Here, we asked whether OSM regulates apoptosis of normal or transformed (osteosarcoma) osteoblasts. We show that OSM sensitizes cells to apoptosis induced by various death inducers such as staurosporine, ultraviolet or tumor necrosis factor-a. Apoptosis is mediated by the mitochondrial pathway, with release of cytochrome c from the mitochondria to the cytosol and activation of caspases-9 and -3. DNA micro-arrays revealed that OSM modulates the expression of Bax, Bad, Bnip3, Bcl-2 and Mcl-1. Pharmacological inhibitors, dominant-negative signal transducer and activator of transcriptions (STATs), stable RNA interference and knockout cells indicated that the transcription factors p53 and STAT5, which are activated by OSM, are implicated in the sensitization to apoptosis, being responsible for Bax induction and Bcl-2 reduction, respectively. These results indicate that, in addition to growth arrest and induced differentiation, OSM also sensitizes normal and transformed osteoblasts to apoptosis by a mechanism implicating (i) activation and nuclear translocation of STAT5 and p53 and (ii) an increased Bax/Bcl-2 ratio. Therefore, association of OSM with kinase inhibitors such as Sts represents new therapeutic opportunities for wild-type p53 osteosarcoma.

Purpose: 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. Experimental Design: 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 microcomputed 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. Conclusion: 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.Osteosarcomas are rare bone-forming tumors that affect primarily young adults. These cancer cells arise from osteoblasts, the cells responsible for bone apposition. Rather than a unique gene alteration, multiple deregulations of the proteins controlling the G 1 -S-phase cell cycle checkpoint (p53, Rb, p16INK4A , MDM2, etc.) are involved in the pathogenesis and chemoresistance of osteosarcomas (1, 2). Although the prognosis and chemotherapies of patients with osteosarcoma were improved significantly in the seventies, the survival rate after 5 years is only 60% to 70% and as low as 30% when pulmonary metastases are detected at diagnosis. These survival rates were not further ameliorated during the past decades (3, 4).Thus, new therapies that inhibit the growth or metastasis of these tumors will have a significant effect on patient survival. Cytokines of the interleukin-6 (IL-6) family, such as oncostatin M (OSM), are recognized as pleiotropic factors influencing many pathophysiologic events in several organs, including bone (5 -8). These cytokines have all been reported to stimulate osteoclastogenesis and, in some cases, to stimulate osteoblast differentiation in cell cultures. However, recent in vivo and genetic data have challenged these concepts (reviewed in refs. 5 -8). For example, transgenic mice overexpressing IL-6 showed a decrease in osteobla...

The cytokine Oncostatin M (OSM) is cytostatic, pro-apoptotic and induces differentiation of osteosarcoma cells into osteocytes, suggesting new adjuvant treatment for these bone-forming sarcomas. However, OSM systemic over-expression could lead to adverse side effects such as generalized inflammation, neoangiogenesis and osteolysis. We determine here the effect of OSM on chondrosarcoma, another primary bone sarcoma characterized by the production of cartilage matrix and altered bone remodelling. Chondrosarcomas are resistant to conventional chemotherapy and radiotherapy, and wide surgical excision remains the only available treatment. We found that OSM blocked the cell cycle in four of five chondrosarcoma cell lines, independently of p53 and presumably through the JAK3/STAT1 pathway. In two tested cell lines, OSM induced a hypertrophic chondrocyte differentiation, with an induced Cbfa1/SOX9 ratio and induced Coll10, matrix metalloproteinase 13 (MMP13) and RANKL expression. Adenoviral gene transfer of OSM (AdOSM) in the Swarm rat chondrosarcoma (SRC) model indicated that local intra-tumoral OSM over-expression reduces chondrosarcoma development not only with reduced tumor proliferation and enhanced apoptosis but also with enhanced RANKL expression, osteoclast formation and reduced bone volumes. Flu-like symptoms were induced by the AdOSM, but there was no effect on tumor angiogenesis. Therefore, OSM could be considered as a new adjuvant anti-cancer agent for chondrosarcomas. A local application of this cytokine is presumably needed to overcome the poor vascularization of these tumors and to limit the deleterious effect on other tissues. Its side effect on bone remodeling could be managed with anti-resorption agents, thus offering potential new lines of therapeutic interventions.

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