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Biomedicines Dec 2019Oncostatin M (OSM), as one of the gp130/IL-6 family of cytokines, interacts with receptor complexes that include the gp130 signaling molecule and OSM receptor β OSMRβ... (Review)
Review
Oncostatin M (OSM), as one of the gp130/IL-6 family of cytokines, interacts with receptor complexes that include the gp130 signaling molecule and OSM receptor β OSMRβ chain subunits. OSMRβ chains are expressed relatively highly across a broad array of connective tissue (CT) cells of the lung, such as fibroblasts, smooth muscle cells, and epithelial cells, thus enabling robust responses to OSM, compared to other gp130 cytokines, in the regulation of extracellular matrix (ECM) remodeling and inflammation. OSMRβ chain expression in lung monocyte/macrophage populations is low, whereas other receptor subunits, such as that for IL-6, are present, enabling responses to IL-6. OSM is produced by macrophages and neutrophils, but not CT cells, indicating a dichotomy of OSM roles in macrophage verses CT cells in lung inflammatory disease. ECM remodeling and inflammation are components of a number of chronic lung diseases that show elevated levels of OSM. OSM-induced products of CT cells, such as MCP-1, IL-6, and PGE2 can modulate macrophage function, including the expression of OSM itself, indicating feedback loops that characterize Macrophage and CT cell interaction.
PubMed: 31817403
DOI: 10.3390/biomedicines7040095 -
The Journal of Pathology May 2022Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease. Here we investigated the role...
Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH-related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial-to-mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH-related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro-carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Oncostatin M
PubMed: 35064579
DOI: 10.1002/path.5871 -
Cancers Aug 2022Primary liver cancers represent the third-most-common cause of cancer-related mortality worldwide, with an incidence of 80-90% for hepatocellular carcinoma (HCC) and... (Review)
Review
Primary liver cancers represent the third-most-common cause of cancer-related mortality worldwide, with an incidence of 80-90% for hepatocellular carcinoma (HCC) and 10-15% for cholangiocarcinoma (CCA), and an increasing morbidity and mortality rate. Although HCC and CCA originate from independent cell populations (hepatocytes and biliary epithelial cells, respectively), they develop in chronically inflamed livers. Evidence obtained in the last decade has revealed a role for cytokines of the IL-6 family in the development of primary liver cancers. These cytokines operate through the receptor subunit gp130 and the downstream Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. Oncostatin M (OSM), a member of the IL-6 family, plays a significant role in inflammation, autoimmunity, and cancer, including liver tumors. Although, in recent years, therapeutic approaches for the treatment of HCC and CCA have been implemented, limited treatment options with marginal clinical benefits are available. We discuss how OSM-related pathways can be selectively inhibited and therapeutically exploited for the treatment of liver malignancies.
PubMed: 36077744
DOI: 10.3390/cancers14174211 -
Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA.Journal of Neurochemistry Jun 2021Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE . Priming has gained interest as a mechanism...
Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE . Priming has gained interest as a mechanism underlying the transition to chronic pain. Which stimuli induce priming and what cellular mechanisms are employed remains incompletely understood. In adult male rats, we present the cytokine Oncostatin M (OSM), a member of the IL-6 family, as an inducer of priming by a novel mechanism. We used a high content microscopy based approach to quantify the activation of endogenous PKA-II and ERK of thousands sensory neurons in culture. Incubation with OSM increased and prolonged ERK activation by agents that increase cAMP production such as PGE , forskolin, and cAMP analogs. These changes were specific to IB4/CaMKIIα positive neurons, required protein translation, and increased cAMP-to-ERK signaling. In both, control and OSM-treated neurons, cAMP/ERK signaling involved RapGEF2 and PKA but not Epac. Similar enhancement of cAMP-to-ERK signaling could be induced by GDNF, which acts mostly on IB4/CaMKIIα-positive neurons, but not by NGF, which acts mostly on IB4/CaMKIIα-negative neurons. In vitro, OSM pretreatment rendered baseline TTX-R currents ERK-dependent and switched forskolin-increased currents from partial to full ERK-dependence in small/medium sized neurons. In summary, priming induced by OSM uses a novel mechanism to enhance and prolong coupling of cAMP/PKA to ERK1/2 signaling without changing the overall pathway structure.
Topics: Animals; Antineoplastic Agents; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Guanine Nucleotide Exchange Factors; Humans; Hyperalgesia; MAP Kinase Signaling System; Male; Mice; Oncostatin M; Rats; Rats, Sprague-Dawley
PubMed: 32885411
DOI: 10.1111/jnc.15172 -
The Journal of Clinical Investigation Oct 2022
Topics: Breast Neoplasms; Cell Line, Tumor; Female; Humans; Oncostatin M; Stromal Cells; Tumor Microenvironment
PubMed: 36169029
DOI: 10.1172/JCI165107 -
Stem Cell Research & Therapy Jun 2022Oncostatin M receptor (OSMR), as one of the receptors for oncostatin M (OSM), has previously been shown to mediate the stimulatory role of OSM in osteoclastogenesis and...
BACKGROUND
Oncostatin M receptor (OSMR), as one of the receptors for oncostatin M (OSM), has previously been shown to mediate the stimulatory role of OSM in osteoclastogenesis and bone resorption. However, it remains to be clarified whether and how OSMR affects the differentiation of osteoblasts.
METHODS
The expression level of OSMR during osteoblast and adipocyte differentiation was examined. The role of OSMR in the differentiation was investigated using in vitro gain-of-function and loss-of-function experiments. The mechanisms by which OSMR regulates bone cell differentiation were explored. Finally, in vivo function of OSMR in cell fate determination and bone homeostasis was studied after transplantation of OSMR-silenced bone marrow stromal cells (BMSCs) to the marrow of ovariectomized mice.
RESULTS
OSMR was regulated during osteogenic and adipogenic differentiation of marrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. OSMR suppressed osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. Mechanistic investigations showed that OSMR inhibited extracellular signal-regulated kinase (ERK) and autophagy signaling. The downregulation of autophagy, which was mediated by ERK inhibition, suppressed osteogenic differentiation of progenitor cells. Additionally, inactivation of ERK/autophagy signaling attenuated the stimulation of osteogenic differentiation induced by Osmr siRNA. Furthermore, transplantation of BMSCs in which OSMR was silenced to the marrow of mice promoted osteoblast differentiation, attenuated fat accumulation and osteoclast differentiation, and thereby relieved the osteopenic phenotype in the ovariectomized mice.
CONCLUSIONS
Our study has for the first time established the direct role of OSMR in regulating osteogenic differentiation of marrow stromal progenitor cells through ERK-mediated autophagy signaling. OSMR thus contributes to bone homeostasis through dual regulation of osteoblasts and osteoclasts. It also suggests that OSMR may be a potential target for the treatment of metabolic disorders such as osteoporosis.
Topics: Animals; Autophagy; Cell Differentiation; Extracellular Signal-Regulated MAP Kinases; MAP Kinase Signaling System; Mice; Oncostatin M Receptor beta Subunit; Osteoblasts; Osteogenesis
PubMed: 35765036
DOI: 10.1186/s13287-022-02958-1 -
Frontiers in Immunology 2020Adipocytes are the largest cell type in terms of volume, but not number, in adipose tissue. Adipocytes are prominent contributors to systemic metabolic health. Obesity,... (Review)
Review
Adipocytes are the largest cell type in terms of volume, but not number, in adipose tissue. Adipocytes are prominent contributors to systemic metabolic health. Obesity, defined by excess adipose tissue (AT), is recognized as a low-grade chronic inflammatory state. Cytokines are inflammatory mediators that are produced in adipose tissue (AT) and function in both AT homeostatic as well as pathological conditions. AT inflammation is associated with systemic metabolic dysfunction and obesity-associated infiltration and proliferation of immune cells occurs in a variety of fat depots in mice and humans. AT immune cells secrete a variety of chemokines and cytokines that act in a paracrine manner on adjacent adipocytes. TNFα, IL-6, and MCP-1, are well studied mediators of AT inflammation. Oncostatin M (OSM) is another proinflammatory cytokine that is elevated in AT in human obesity, and its specific receptor (OSMRβ) is also induced in conditions of obesity and insulin resistance. OSM production and paracrine signaling in AT regulates adipogenesis and the functions of AT. This review summarizes the roles of the oncostatin M receptor (OSMRβ) as a modulator of adipocyte development and function its contributions to immunological adaptations in AT in metabolic disease states.
Topics: Adipocytes; Adipose Tissue; Animals; Energy Metabolism; Homeostasis; Humans; Inflammation Mediators; Insulin Resistance; Obesity; Oncostatin M; Oncostatin M Receptor beta Subunit; Panniculitis; Signal Transduction
PubMed: 33854494
DOI: 10.3389/fimmu.2020.612013 -
Arthritis Research & Therapy May 2021Informative serum biomarkers for monitoring inflammatory activity and treatment responses in axial spondyloarthritis (axSpA) are lacking. We assessed whether Lipocalin 2...
BACKGROUND
Informative serum biomarkers for monitoring inflammatory activity and treatment responses in axial spondyloarthritis (axSpA) are lacking. We assessed whether Lipocalin 2 (LCN2) and Oncostatin M (OSM), both having roles in inflammation and bone remodeling, may accurately reflect chronic joint inflammation and treatment response in axSpA. Previous reports in animal models showed involvement of LCN2 and OSM in joint/gut inflammation. We asked whether they also play a role in human axSpA.
METHODS
We analyzed a longitudinal observational axSpA cohort (286 patients) with yearly clinical assessments and concurrent measurements of serum LCN2 and OSM (1204 serum samples) for a mean of 4 years. Biomarker levels were correlated with MRI scoring and treatment response.
RESULTS
Persistent and transient elevation of LCN2 and OSM were observed in axSpA patients. Persistent elevation of LCN2 or OSM, but not CRP, correlated with sacroiliac joint (SIJ) MRI SPARCC scores (Pearson's correlation p = 0.0005 and 0.005 for LCN2 and OSM respectively), suggesting that LCN2/OSM outperforms CRP as reflective of SIJ inflammation. We observed both concordant and discordant patterns of LCN2 and OSM in relationship to back pain, the cardinal clinical symptom in axSpA. Twenty-six percent (73/286) of the patients remained both clinically and serologically active (CASA). Sixty percent (173/286) of the patients became clinically quiescent, with back pain resolved, but 53% (92/173) of them were serologically active (CQSA), indicating that pain control may not indicate control of joint inflammation, as reflected by positive MRI imaging of SIJ. With respect to treatment responses, transient elevation of LCN2 or OSM over time was predictive of better response to all treatments.
CONCLUSION
In axSpA, persistent LCN2 and/or OSM elevation reflects chronic SIJ inflammation and suboptimal treatment response. In our cohort, half of the currently deemed clinically quiescent patients with back pain resolved continued to demonstrate chronic joint inflammation. LCN2 and OSM profiling outperforms CRP as a predictive measure and provides an objective assessment of chronic local inflammation in axSpA patients.
Topics: Humans; Inflammation; Lipocalin-2; Magnetic Resonance Imaging; Oncostatin M; Sacroiliac Joint; Severity of Illness Index; Spondylarthritis
PubMed: 33990221
DOI: 10.1186/s13075-021-02521-y -
Cancers Dec 2022Despite improvements in preventative strategies, such as regular screenings with Pap tests and human papillomavirus (HPV) tests as well as HPV vaccinations, effective...
Despite improvements in preventative strategies, such as regular screenings with Pap tests and human papillomavirus (HPV) tests as well as HPV vaccinations, effective treatment for advanced cervical cancer remains poor. Deregulation of STAT3 is an oncogenic factor that promotes tumorigenesis and epithelial-to-mesenchymal transition (EMT) in various cancers. Oncostatin M (OSM), a pleiotropic cytokine, induces STAT3 activation, exacerbating cervical cancer. However, the mechanism by which the OSM-STAT3 axis epigenetically regulates tumor-progression-related genes in cervical cancer is not well understood. Here, we show that OSM-mediated STAT3 activation promotes pro-tumorigenic gene expression programs, with chromatin remodeling in cervical cancer. Reanalysis of scRNA-seq data performed in cervical cancer uncovered an interaction between the oncostatin M receptor (OSMR) on tumor cells and OSM induced by tumor-associated macrophages (TAMs). Our gene expression profiling (bulk RNA-seq) shows that OSM-induced genes were involved in hypoxia, wound healing, and angiogenesis, which were significantly inhibited by SD-36, a STAT3-selective degrader. Additionally, ATAC-seq experiments revealed that STAT3 binding motifs were preferentially enriched in open chromatin regions of the OSM-STAT3-regulated genes. Among the 50 candidate genes that were regulated epigenetically through the OSM-STAT3 axis, we found that the expression levels of , and were significantly correlated with those of and in three independent cervical cancer cohorts. Also, higher expression levels of these genes are significantly associated with poor prognosis in cervical cancer patients. Collectively, our findings demonstrate that the OSM-STAT3 signaling pathway regulates crucial transcriptomic programs through epigenetic changes and that selective inhibition of STAT3 may be a novel therapeutic strategy for patients with advanced cervical cancer.
PubMed: 36551576
DOI: 10.3390/cancers14246090 -
BioRxiv : the Preprint Server For... Dec 2023Antiviral immune mediators, including interferons and their downstream effectors, are critical for host defense yet can become detrimental when uncontrolled. Here, we...
Antiviral immune mediators, including interferons and their downstream effectors, are critical for host defense yet can become detrimental when uncontrolled. Here, we identify a macrophage-mediated anti-inflammatory mechanism that limits type I interferon (IFN-I) responses. Specifically, we found that cellular stress and pathogen recognition induce Oncostatin M (OSM) production by macrophages. OSM-deficient mice succumbed to challenge with influenza or a viral mimic due to heightened IFN-I activation. Macrophage-derived OSM restricted excessive IFN-I production by lung epithelial cells following viral stimulation. Furthermore, reconstitution of OSM in the respiratory tract was sufficient to protect mice lacking macrophage-derived OSM against morbidity, indicating the importance of local OSM production. This work reveals a host strategy to dampen inflammation in the lung through the negative regulation of IFN-I by macrophages.
PubMed: 38168230
DOI: 10.1101/2023.12.16.572019