The dual role of IL-6-type cytokines on bone remodeling and bone tumors

Blanchard, Frédéric; Duplomb, Laurence; Baud’huin, Marc; Brounais, Bénédicte

doi:10.1016/j.cytogfr.2008.11.004

Cited by 180 publications

(164 citation statements)

References 67 publications

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“…15 In contrast, murine OSM signals only through the gp130þOSMR complex. 15 Binding of OSM to these receptors activates intracellular signalling proteins, mainly JAK1, JAK2, JAK3, STAT1, STAT3, the MAP kinase pathway as well as the PI3K/AKT cascade. 15,22 OSM is mainly produced by macrophages, neutrophils and T lymphocytes.…”

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confidence: 99%

“…13,14 Oncostatin M (OSM) is a pro-inflammatory cytokine of the IL-6 family which is composed of nine members such as IL-27 and leukemia inhibitory factor (LIF). 15 OSM has cytostatic activities on sarcoma and carcinoma cell lines, [15][16][17] activates endothelial cells, 18 induces acute phase proteins production by liver as well as inflammatory and immune responses in various tissues such as skin, lung and bone/cartilage. 15,19,20 In human, this pleiotropic cytokine can bind to the type I heterodimeric receptor composed of gp130 and LIF receptor (LIFR) 21 or to the type II receptor composed of gp130 and OSMR.…”

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confidence: 99%

“…15,19,20 In human, this pleiotropic cytokine can bind to the type I heterodimeric receptor composed of gp130 and LIF receptor (LIFR) 21 or to the type II receptor composed of gp130 and OSMR. 15 In contrast, murine OSM signals only through the gp130þOSMR complex. 15 Binding of OSM to these receptors activates intracellular signalling proteins, mainly JAK1, JAK2, JAK3, STAT1, STAT3, the MAP kinase pathway as well as the PI3K/AKT cascade.…”

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confidence: 99%

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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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Direct anti‐cancer effect of oncostatin M on chondrosarcoma

David

Guihard

Brounais

et al. 2011

Intl Journal of Cancer

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“…Consequently, if certain a gene(s) in this region is (are) important for correct calcitonin release or function, an influence on bone mineral traits can be hypothesised. For the QTL affecting BMC and Lean at chr6: 24 770 684-26 159 346 bp, the genes EDC4 and NFATC3 may serve as candidate genes for bone mineral traits for the following reasons: according to Seto et al (2015), the assembly of EDC4 and Dcp1a into processing bodies is critical for the translational regulation of IL-6, which plays a dual role in bone remodelling and bone tumours (Franchimont et al, 2005;Blanchard et al, 2009). Additionally, heterozygous EDC4 knockout mice showed a change in bone density, though it was not significant (Origins of bone and cartilage disease project, 2015).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide QTL mapping results for regional DXA body composition and bone mineral density traits in pigs

Bernau¹,

Kremer-Rücker

Međugorac³

et al. 2017

Arch. Anim. Breed.

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Abstract. In a previous study, genome-wide mapping of quantitative trait loci (QTL) for five body composition traits, three bone mineral traits and live weight was performed using whole-body dual-energy X-ray absorptiometry (DXA) data. Since QTL for bone mineral traits were rare, the current study aimed to clarify whether the mapping results were influenced by the analysed body regions. Thus, the same material (551 pigs) and methods as in the whole-body QTL mapping study were used. However, for evaluation of the DXA scans, we manually defined two body regions: (i) from the last ribs to the pelvis (A) and (ii) including the pelvis and the hind limbs (P). Since live weight was not affected by the regional analysis, it was omitted from the QTL mapping design.Our results show an overall high consistency of mapping results especially for body composition traits. Two thirds of the initial whole-body QTL are significant for both A and P. Possible causes for the still low number of bone mineral QTL and the lower consistency found for these traits are discussed. For body composition traits, the data presented here show high genome-wide Pearson correlations between mapping results that are based on DXA scans with the time-saving "whole-body standard setting" and mapping results for DXA data that were obtained by time-consuming manual definition of the regions of interest. However, our results also suggest that whole-body or regional DXA scans might generally be less suitable for mapping of bone mineral traits in pigs. An analysis of single reference bones could be more useful.

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“…IL-6 family cytokines appear to be double-edged swords, since the development of bone cancers may be either prevented or enhanced by this family of cytokines, depending on the cell type, the stage of the tumor and the bone environment (45). Observed downregulation of IL-6 in the human JJ012 chondrosarcoma cell line compared with the chondrocytes supports the hypothesis that IL-6 is acting as a differentiation/anti-inflammatory factor in this cellular context, indicating the possibility that a factor(s) or interacting proteins in the tumor have the ability to inhibit IL-6 expression.…”

Section: Discussionmentioning

confidence: 99%

Effect of cytostatic proline rich polypeptide-1 on tumor suppressors of inflammation pathway signaling in chondrosarcoma

Galoian

Luo

Qureshi

et al. 2016

Molecular and Clinical Oncology

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Abstract. Cytokines produced in the tumour microenvironment exert an important role in cancer pathogenesis and in the inhibition of disease progression. Cancer of the cartilage is termed metastatic chondrosarcoma; however, the signaling events resulting in mesenchymal cell transformation to sarcoma have yet to be fully elucidated. The present study aimed to characterize the cytokine expression profile in the human JJ012 chondrosarcoma cell line, as well as the effect of cytostatic proline-rich polypeptide-1 (PRP-1). Western blot experiments demonstrated that the levels of suppressor of cytokine signaling 3 (SOCS3) were upregulated in chondrocytes compared with chondrosarcoma cells. Addition of PRP-1 restored the expression of the tumor suppressors, SOCS3 and ten-eleven-translocation methylcytosine dioxygenase 1 and 2 (TET1/2), in a dose-responsive manner. It is known that methylation of histone H3K9 was eliminated from the promoters of the inflammation-associated genes. PRP-1 inhibited H3K9 demethylase activity with an IC 50 (concentration required to give half-maximal inhibition) value of 3.72 µg/ml in the chondrosarcoma cell line. Data obtained from ELISA experiments indicated that the expression of interleukin-6 (IL-6) in chondrosarcoma cells was 86-fold lower compared with that in C28 chondrocytes. In the present study, a 53-fold downregulation of IL-6 expression in co-culture of chondrosarcoma cells and C28 chondrocytes was identified as well. Downregulation of IL-6 expression has been documented in numerous other tumor types, although the reasons for this have not been fully established. In chondrosarcoma, IL-6 manifests itself as an anti-inflammatory agent and, possibly, as an anti-tumorigenic factor. To explore protein-DNA interactions leading to such differences, a gel-shift chemiluminescent assay was performed. Gel shifts were observed for chondrosarcoma and chondrocytes in the lanes that contained nuclear cell extract and oligo-IL-6 DNA. Notably, the DNA-protein complexes in C28 chondrocytes were markedly larger compared with those in chondrosarcoma cells. The mechanisms that underpin such differences, and characterization of the interacting proteins, remain to be fully elucidated.

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The dual role of IL-6-type cytokines on bone remodeling and bone tumors

Cited by 180 publications

References 67 publications

Direct anti‐cancer effect of oncostatin M on chondrosarcoma

Direct anti‐cancer effect of oncostatin M on chondrosarcoma

Genome-wide QTL mapping results for regional DXA body composition and bone mineral density traits in pigs

Effect of cytostatic proline rich polypeptide-1 on tumor suppressors of inflammation pathway signaling in chondrosarcoma

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