Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

Hoermann, Gregor; Cerny-Reiterer, Sabine; Perné, Andrea; Klauser, Miriam; Höetzenecker, Konrad; Klein, Katharina; Müllauer, Leonhard; Gröger, Marion; Nijman, Sebastian M.; Klepetko, Walter; Valent, Peter; Mayerhofer, Matthias

doi:10.1016/j.ajpath.2011.01.020

Cited by 38 publications

(64 citation statements)

References 49 publications

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“…The IL-6 family, including OSM, plays an anti-inflammatory role, and LIF, another member of the IL-6 family, also has antiinflammatory activity (22). Activation of STAT3 and STAT5 is associated with OSM expression (9,10). In this study, we found that OSM suppressed Th17 cell differentiation but induced Treg cell differentiation through the conversion of Treg into Th17 cells.…”

Section: Discussionmentioning

confidence: 52%

“…It has recently been found to be involved in the expression of transcription factors associated with inflammatory and immune responses mediated by T cells (9,10). However, few studies have reported the effects of OSM on the proliferation of Th17 and Treg cells.…”

Section: Discussionmentioning

confidence: 99%

“…OSM has both proinflammatory and anti-inflammatory activities (8), and is associated with the activation of transcription factors, including the activation of STAT3 (9). OSM production is mediated by activation of STAT5: STAT5 activation induces OSM expression and deletion of STAT5 decreases OSM expression (10).…”

mentioning

confidence: 99%

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Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells

Son

Lee

Kim

et al. 2017

The Journal of Immunology

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Oncostatin M (OSM) is a pleiotropic cytokine and a member of the IL-6 family. It has both proinflammatory and anti-inflammatory functions and is involved in the activation of STAT3 and STAT5. Rheumatoid arthritis is an autoimmune disease that causes chronic and excessive inflammation. Rheumatoid arthritis can lead to induction of Th17 cells, which express IL-17. The aim of this study was to measure the effects of OSM on the proliferation of regulatory T cells and Th17 cells from mice. IL-2 immune complex suppressed the development of collagen-induced arthritis in mice and altered the regulatory T/Th17 cell balance by increasing OSM expression. OSM mitigated the proliferation of Th17 cells and decreased the expression of IL-17 and IL-21. It promoted the activation of suppressor of cytokine signaling 3 (SOCS3), STAT3, and STAT5. Inhibition of SOCS3, STAT3, and STAT5 lessened the OSM-induced reduction in proliferation of Th17 cells. These observations suggest that OSM can inhibit Th17 differentiation by reciprocally controlling SOCS3, STAT3, and STAT5.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells

Son

Lee

Kim

et al. 2017

The Journal of Immunology

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“…Recent studies have indicated that OSM can maintain bone formation by means of OSM Receptor (OSMR) and STAT3, which acts on the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitor cells (Guihard et al 2015). OSM can stimulate the growth of endothelial cells, fibroblasts and osteoblasts, which indicates that OSM may be a key regulator of the marrow microenvironment, which is helpful to the formation of bone (Hoermann et al 2011). These studies support our present finding that OSM has a potent stimulatory effect on the osteogenic differentiation of DPSCs.…”

Section: Discussionmentioning

confidence: 99%

The role of oncostatin M regulates osteoblastic differentiation of dental pulp stem cells through STAT3 pathway

et al. 2016

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Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells, which have the selfrenewal and multi-lineage differentiation potential, including chondrocytes, adipocytes, neural cells and osteoblasts. So they play a significant role in pulp repair and bone regeneration. Oncostatin M (OSM), one of the IL-6 family cytokines, inhibits adipogenic differentiation and stimulates osteogenic differentiation of human bone marrow mesenchymal stem cells. However, the effect of OSM on DPSCs is unclear. We found that OSM induced osteogenic differentiation of DPSCs, promoting matrix mineralization as measured by Alizarin Red S staining. OSM also increased expression of osteogenesis-associated gene products Alkaline phosphatase, Bone morphogenetic protein 2 (BMP2), Runt-related transcription factor 2 and Osteocalcin (OCN) as assessed by immunoblotting. We also found that OSM activated the Signal Transducer And Activator Of Transcription 3 (STAT3) pathway during the osteogenic differentiation of DPSCs. Blocking the osteogenic differentiation by silencing of STAT3 can significantly inhibit OSMinduced osteogenic differentiation of DPSCs and the expression of related genes, furthermore matrix mineralization was also suppressed. In summary, OSM promotes osteoblastic differentiation of DPSCs and osteogenesis-related genes expression through the JAK3/STAT3 signaling pathway which may be useful for the autologous transplantation of DPSCs.

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“…Lentiviral transfection of HMC-1.2 cells with shRNA against FES was performed as described (45). A detailed description is provided in the Supplement.…”

Section: Knock-down Of Fes In Hmc-12 Cellsmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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Proteomic-based drug testing is an emerging approach to establish the clinical value and antineoplastic potential of multi-kinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction-profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC 50 values. Midostaurin and CGP62221 also produced growth-inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, that accumulates in vivo, showed no substantial effects.Chemical proteomic profiling and drug-competition experiments revealed that midostaurin interacts with KIT and several additional kinase-targets. The key downstream-regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgEreceptor-downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

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Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

Cited by 38 publications

References 49 publications

Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells

Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells

The role of oncostatin M regulates osteoblastic differentiation of dental pulp stem cells through STAT3 pathway

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

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