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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 -
Molecular Metabolism Dec 2021Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into...
OBJECTIVE
Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state.
METHODS
Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively.
RESULTS
Inguinal WAT of HFD-fed gp130 mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = -0.413, p < 0.001, n = 66).
CONCLUSIONS
Our data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity.
Topics: 3T3-L1 Cells; Adipocytes, White; Animals; Cells, Cultured; Cytokine Receptor gp130; Humans; Male; Mice; Oncostatin M; STAT3 Transcription Factor
PubMed: 34547509
DOI: 10.1016/j.molmet.2021.101341 -
Inflammatory Bowel Diseases Oct 2021Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF)...
BACKGROUND
Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD.
METHODS
We collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05.
RESULTS
Newly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages.
CONCLUSIONS
We found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making.
Topics: Biomarkers; Colitis; Crohn Disease; Humans; Inflammatory Bowel Diseases; Oncostatin M; Prognosis; Tumor Necrosis Factor Inhibitors
PubMed: 33624092
DOI: 10.1093/ibd/izab032 -
Experimental Physiology Jul 2020What is the central question of this study? What controls the proliferation and apoptosis in the pathogenesis of psoriasis? What is the main finding and its importance?...
NEW FINDINGS
What is the central question of this study? What controls the proliferation and apoptosis in the pathogenesis of psoriasis? What is the main finding and its importance? The pathogenesis psoriasis involves abnormal homeostasis of keratinocytes, with hyperproliferation and decreasing apoptosis. An inhibitor of apoptosis protein family molecule, Livin, is highly expressed in psoriasis vulgaris lesional skin tissue. Expression of Livin was upregulated at transcription and protein levels after stimulation with oncostatin M (OSM). OSM promoted the survival of HaCaT cells in oxidative stress conditions. Expression of Livin and proliferation of HaCaT cells stimulated by OSM was regulated through ERK and STAT3 signalling pathways. This study might provide new insights into targeted therapy for psoriasis.
ABSTRACT
Psoriasis is an immune-mediated chronic inflammatory disease. Abnormal homeostasis of keratinocytes, with hyperproliferation and decreasing apoptosis, is involved in the pathogenesis of psoriasis. Here, we report that an inhibitor of apoptosis protein family molecule, Livin, is highly expressed in psoriasis vulgaris lesional skin tissue at transcription and protein levels. Importantly, the expression level of Livin is related to the severity of psoriasis. The aim of the study was to investigate the regulation and functions of Livin in keratinocytes stimulated by the pro-inflammatory cytokine oncostatin M (OSM). The expression of Livin in HaCaT cells at mRNA and protein levels was measured by real-time PCR and Western blotting after OSM stimulation. The cell proliferation was measured by a 5-ethynyl-2'-deoxyuridine incorporation assay. Cell death was induced by the exogenous hydrogen peroxide (H O ) stress model, detected by 7-amino-actinomycin D staining and analysed by flow cytometry. Livin was overexpressed by a lentiviral transduction system to validate the roles of OSM and Livin in HaCaT cells. Specific inhibitors of ERK (U0126) and STAT3 (cryptotanshinone) were applied to investigate the signalling pathways involved in the regulation of Livin expression by OSM. The expression of Livin was upregulated after stimulation with OSM. OSM promoted the proliferation and survival of HaCaT cells. The expression of Livin and the proliferation of HaCaT cells induced by OSM were regulated through the ERK and STAT3 signalling pathways. We conclude that OSM promotes HaCaT cell proliferation and survival in conditions of oxidative stress.
Topics: Adaptor Proteins, Signal Transducing; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; HaCaT Cells; Humans; Inhibitor of Apoptosis Proteins; Keratinocytes; Neoplasm Proteins; Oncostatin M; Oxidative Stress; Psoriasis; STAT3 Transcription Factor; Signal Transduction; Up-Regulation
PubMed: 32359099
DOI: 10.1113/EP088584 -
Pharmacology 2023Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and...
Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas.
INTRODUCTION
Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far.
METHODS
The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies.
RESULTS
The proportion of peripheral CD45+ cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8+ T cells. In tumor tissues, CD8+ T cell and CD45‒ TRAIL+ cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma.
CONCLUSION
In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs.
Topics: Humans; Oncostatin M; Nivolumab; Leiomyosarcoma; Cohort Studies; Liposarcoma; T-Lymphocytes; Tumor Microenvironment
PubMed: 36996792
DOI: 10.1159/000529811 -
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 -
Archives of Endocrinology and Metabolism Feb 2020Objective Activated macrophages (M1-type macrophages) in adipose tissue secrete many proinflammatory cytokines that induce insulin resistance (IR). Oncostatin M (OSM), a...
Objective Activated macrophages (M1-type macrophages) in adipose tissue secrete many proinflammatory cytokines that induce insulin resistance (IR). Oncostatin M (OSM), a member of the interleukin-6 (IL-6) family of Gp130 cytokines, plays an important role in a variety of biological functions, including the regulation of inflammatory responses. Proinflammatory cytokines released in patients with IR trigger a chronic, low-grade inflammatory reaction in blood vessel walls. This inflammator response leads to endothelial damage, which is the main mechanism for atherosclerosis and many cardiovascular diseases. Animal studies have reported a relationship between OSM and IR. To the best of our knowledge, however, few clinical studies have examined this topic. Therefore, we studied the relationship between serum levels of OSM and IR. Subjects and methods This prospective cross-sectional case-control study enrolled 50 people with IR (according to the HOMA-IR and QUICKI indices) and 34 healthy controls. The fasting blood concentrations of insulin, glucose, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, total cholesterol, C-reactive protein (CRP), and OSM were determined. Results There were no significant differences between the two groups in age, sex, and HbA1c levels. Univariate analyses showed that waist circumference (WC) and levels of fasting glucose, insulin, CRP, HDL-C, OSM, HOMA-IR, and QUICKI differed between the two study groups. In multivariate analyses, both IR indices (QUICKI and HOMA) and OSM differed between the two groups. Conclusion OSM was correlated with the IR indices (QUICKI and HOMA). For simplicity, it might replace the other IR indices in the future. Further detailed studies are needed to confirm this.
Topics: Adult; Aged; Case-Control Studies; Chronic Disease; Cross-Sectional Studies; Female; Humans; Inflammation; Insulin Resistance; Male; Middle Aged; Oncostatin M; Pilot Projects; Prospective Studies
PubMed: 31576964
DOI: 10.20945/2359-3997000000176 -
International Journal of Molecular... Mar 2022Oncostatin M (OSM), which belongs to the IL-6 family of cytokines, is the most potent and effective stimulator of osteoclast formation in this family, as assessed by... (Review)
Review
Oncostatin M (OSM), which belongs to the IL-6 family of cytokines, is the most potent and effective stimulator of osteoclast formation in this family, as assessed by different in vitro assays. Osteoclastogenesis induced by the IL-6 type of cytokines is mediated by the induction and paracrine stimulation of the osteoclastogenic cytokine receptor activator of nuclear factor κ-B ligand (RANKL), expressed on osteoblast cell membranes and targeting the receptor activator of nuclear factor κ-B (RANK) on osteoclast progenitor cells. The potent effect of OSM on osteoclastogenesis is due to an unusually robust induction of RANKL in osteoblasts through the OSM receptor (OSMR), mediated by a JAK-STAT/MAPK signaling pathway and by unique recruitment of the adapter protein Shc1 to the OSMR. Gene deletion of in mice results in decreased numbers of osteoclasts and enhanced trabecular bone caused by increased trabecular thickness, indicating that OSM may play a role in physiological regulation of bone remodeling. However, increased amounts of OSM, either through administration of recombinant protein or of adenoviral vectors expressing , results in enhanced bone mass due to increased bone formation without any clear sign of increased osteoclast numbers, a finding which can be reconciled by cell culture experiments demonstrating that OSM can induce osteoblast differentiation and stimulate mineralization of bone nodules in such cultures. Thus, in vitro studies and gene deletion experiments show that OSM is a stimulator of osteoclast formation, whereas administration of OSM to mice shows that OSM is not a strong stimulator of osteoclastogenesis in vivo when administered to adult animals. These observations could be explained by our recent finding showing that OSM is a potent stimulator of the osteoclastogenesis inhibitor WNT16, acting in a negative feedback loop to reduce OSM-induced osteoclast formation.
Topics: Animals; Cell Differentiation; Feedback; Interleukin-6; Mice; Oncostatin M; Osteoblasts; Osteoclasts; RANK Ligand; Wnt Proteins
PubMed: 35328707
DOI: 10.3390/ijms23063287 -
The Journal of Investigative Dermatology Mar 2022Impaired re-epithelialization characterized by hyperkeratotic nonmigratory wound epithelium is a hallmark of nonhealing diabetic wounds. In chronic wounds, the copious...
Impaired re-epithelialization characterized by hyperkeratotic nonmigratory wound epithelium is a hallmark of nonhealing diabetic wounds. In chronic wounds, the copious release of oncostatin M (OSM) from wound macrophages is evident. OSM is a potent keratinocyte (KC) activator. This work sought to understand the signal transduction pathway responsible for wound re-epithelialization, the primary mechanism underlying wound closure. Daily topical treatment of full-thickness excisional wounds of C57BL/6 mice with recombinant murine OSM improved wound re-epithelialization and accelerated wound closure by bolstering KC proliferation and migration. OSM activated the Jak-signal transducer and activator of transcription pathway as manifested by signal transducer and activator of transcription 3 phosphorylation. Such signal transduction in the human KC induced TP63, the master regulator of KC function. Elevated TP63 induced ITGB1, a known effector of KC migration. In diabetic wounds, OSM was more abundant than the level in nondiabetic wounds. However, in diabetic wounds, OSM activity was compromised by glycation. Aminoguanidine, a deglycation agent, rescued the compromised KC migration caused by glycated OSM. Finally, topical application of recombinant OSM improved KC migration and accelerated wound closure in db/db mice. This work recognizes that despite its abundance at the wound site, OSM is inactivated by glycation, and topical delivery of exogenous OSM is likely to be productive in accelerating diabetic wound closure.
Topics: Animals; Diabetes Mellitus; Mice; Mice, Inbred C57BL; Oncostatin M; Re-Epithelialization; Wound Healing
PubMed: 34534575
DOI: 10.1016/j.jid.2021.04.039 -
Journal of Leukocyte Biology Nov 2020Oncostatin M (OSM) is a pleiotropic cytokine elevated in a number of inflammatory conditions including periodontal disease. OSM is produced by a variety of immune cells...
Oncostatin M (OSM) is a pleiotropic cytokine elevated in a number of inflammatory conditions including periodontal disease. OSM is produced by a variety of immune cells and has diverse functionality such as regulation of metabolic processes, cell differentiation, and the inflammatory response to bacterial pathogens. The oral cavity is under constant immune surveillance including complementary neutrophil and macrophage populations, due to a persistent symbiotic bacterial presence. Periodontal disease is characterized by a dysbiotic bacterial community, with an abundance of Treponema denticola. Despite strong associations with severe periodontal disease, the source and mechanism of the release of OSM have not been defined in the oral cavity. We show that OSM protein is elevated in the gingival epithelium and immune cell infiltrate during periodontal disease. Furthermore, salivary and oral neutrophil OSM is elevated in correlation with the presence of T. denticola. In an air pouch infection model, T. denticola stimulated higher levels of OSM than the oral pathogen Porphorymonas gingivalis, despite differential recruitment of innate immune cells suggesting T. denticola has distinct properties to elevate OSM levels. OSM release and transcription were increased in isolated human blood, oral neutrophils, or macrophages exposed to T. denticola in vitro as measured by ELISA, qPCR, and microscopy. Using transcription, translation, and actin polymerization inhibition, we found that T. denticola stimulates both OSM release through degranulation and de novo synthesis in neutrophils and also OSM release and synthesis in macrophages. Differential induction of OSM by T. denticola may promote clinical periodontal disease.
Topics: Adult; Aged; Female; Humans; Macrophages; Male; Middle Aged; Neutrophils; Oncostatin M; Treponema denticola; Treponemal Infections
PubMed: 32678942
DOI: 10.1002/JLB.4MA0620-072RR