Downregulation of Osteoblast Markers and Induction of the Glial Fibrillary Acidic Protein by Oncostatin M in Osteosarcoma Cells Require PKCδ and STAT3

Chipoy, Céline; Berreur, Martine; Couillaud, Séverine; Pradal, G; Vallette, François M.; Colombeix, Caroline; Rédini, Françoise; Heymann, Dominique; Blanchard, Frédéric

doi:10.1359/jbmr.040817

Cited by 67 publications

(77 citation statements)

References 47 publications

(74 reference statements)

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“…Growth inhibition by OSM is not always associated with sensitization to apoptosis As indicated before, OSM inhibited [ 3 H]thymidine incorporation in OSRGA and MG63 cells (Table 1; Bellido et al, 1997;Chipoy et al, 2004). Similarly, in both OSRGA ( Figure 3b) and MG63 cells (data not shown; Bellido et al, 1998), p21 WAF1 was transiently induced within 6-24 h of OSM treatment, whereas transient phosphorylation of Rb was observed early after 15 min of cytokine treatment.…”

Section: Proapoptotic Effects Of Osm On Osteosarcoma Cells C Chipoy Esupporting

confidence: 53%

“…These dominant negative STATs were previously shown to prevent various promoters and genes induction in HepG2 and OSRGA cells (Baumann et al, 2000;Chipoy et al, 2004). While neither dnS1 nor dnS3 modified the cell viability, transfection of dnS5b was able to prevent apoptosis induced by OSM þ Sts (Figure 5d).…”

Section: Stat5 Is Necessary For Apoptosis Induced By Osm þ Stsmentioning

confidence: 65%

“…Thus, we tested whether specific kinase inhibitors could also induce apoptosis in association with OSM. Activity and specificity of these kinase inhibitors on signal transduction pathways activated by OSM were described previously (Chipoy et al, 2004). OSRGA cells were pretreated with inhibitors for 1 h and OSM was added or not for 3 days.…”

Section: Proapoptotic Effects Of Osm On Osteosarcoma Cells C Chipoy Ementioning

confidence: 99%

“…We have previously showed that OSM has opposing effects on osteosarcoma or non-transformed osteoblasts, depending on the stage of differentiation (Chipoy et al, 2004). On poorly differentiated cells, OSM enhances osteoblastic markers expression, and their capacity to form mineralized bone nodules.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, OSM induces glial fibrillary acidic protein expression, indicating a glial-like or osteocytic terminal differentiation. The kinase PKCd and the transcription factor STAT3 are implicated in these effects of OSM (Chipoy et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

et al. 2007

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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.

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Section: Proapoptotic Effects Of Osm On Osteosarcoma Cells C Chipoy Esupporting

confidence: 53%

Section: Stat5 Is Necessary For Apoptosis Induced By Osm þ Stsmentioning

confidence: 65%

Section: Proapoptotic Effects Of Osm On Osteosarcoma Cells C Chipoy Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

et al. 2007

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Relevance of a new rat model of osteoblastic metastases from prostate carcinoma for preclinical studies using zoledronic acid

Lamoureux

Ory

Battaglia

et al. 2007

Intl Journal of Cancer

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Animal models that mimic osteoblastic metastases associated with prostate carcinoma are required to improve the therapeutic options in humans. A new model was then developed and characterized in immunocompetent rats. The bisphosphonate zoledronic acid (ZOL) was tested to validate this model as a therapeutic application. Rat AT6-1 prostate tumor cells were characterized in vitro at the transcriptional (bone and epithelial markers) and functional (induction of mineralized nodules) levels. The bone lesions induced after their direct injection into the femur bone marrow were characterized by radiography, microscanner and histology analyses. ZOL effects were studied in vivo on bone lesion development and in vitro on AT6-1 cell proliferation, apoptosis and cell cycle analysis. Apart from epithelial markers, AT6-1 cells express an osteoblast phenotype as they express osteoblastic markers and are able to induce mineralized nodule formation in vitro. A disorganization of the trabecular bone at the growth zone level was observed in vivo after intraosseous AT6-1 cell injection as well as cortical erosion. The tumor itself is associated with bone formation as revealed by SEM analysis and polarized light microscopy. ZOL prevents the development of such osteoblastic lesions, related to a direct inhibitory effect on tumor cell proliferation independent of caspase 3 activation, but associated with cell cycle arrest. A new rat model of osteoblastic bone metastases was validated in immunocompetent rats and used to show the relevance of using ZOL in such lesions, as this compound shows bifunctional effects on both bone remodelling and tumor cell proliferation. ' 2007 Wiley-Liss, Inc.Key words: prostate carcinoma; osteoblastic metastases; experimental model; zoledronic acid Prostate adenocarcinoma, the second leading cause of cancer in men of North America is associated with significant morbidity and mortality due to skeletal metastases that commonly occur in advanced disease, affecting 80-100% of patients. 1,2 Therefore, new therapeutic strategies are needed to improve the prostate cancer patient's outcome. In contrast to bone metastases of breast cancer and myeloma, which are mainly osteolytic, a high percentage of prostate cancer metastases exhibit the radiographic appearance of osteoblastic lesions. 3 To investigate new targets for the development of novel therapies, experimental models that reproduce these osteoblastic bone lesions are required. However, there is a paucity of good preclinical models to study osteoblastic lesions.Animal models are important tools to investigate the pathogenesis and develop treatment strategies for bone metastases in humans. Because spontaneous bone metastasis in animals is uncommon, most animal models of bone metastasis must be derived experimentally. Experimental models of osteolytic, osteoblastic and mixed osteolytic/osteoblastic bone metastases include syngeneic transplantation of spontaneous occurring rodent cancers, chemical induction of cancers in selected strains of rats and mice, newly ...

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Direct anti‐cancer effect of oncostatin M on chondrosarcoma

David

Guihard

Brounais

et al. 2011

Intl Journal of Cancer

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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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Downregulation of Osteoblast Markers and Induction of the Glial Fibrillary Acidic Protein by Oncostatin M in Osteosarcoma Cells Require PKCδ and STAT3

Cited by 67 publications

References 47 publications

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

Relevance of a new rat model of osteoblastic metastases from prostate carcinoma for preclinical studies using zoledronic acid

Direct anti‐cancer effect of oncostatin M on chondrosarcoma

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