Oncostatin M suppresses bone morphogenetic protein-4-induced osteoprotegerin synthesis in MC3T3-E1 osteoblast-like cells: p70 S6 kinase attenuation.

Evidence is accumulating that osteal macrophages, in addition to bone-resorbing osteoclasts and bone-forming osteoblasts, participate vitally in bone remodeling process. Oncostatin M (OSM), an inflammatory cytokine belonging to interleukin-6 superfamily, is recognized as an essential factor secreted by osteal macrophages to orchestrate bone remodeling. Osteoprotegerin (OPG) produced by osteoblasts regulates osteoclastogenesis. We have reported that bone morphogenetic protein-4 (BMP-4) stimulates OPG synthesis in MC3T3-E1 osteoblast-like cells, and that SMAD1/5/8(9), p38 mitogen-activated protein kinase (MAPK), and p70 S6 kinase are involved in the OPG synthesis. The present study aims to investigate the effect of OSM on the synthesis of OPG stimulated by BMP-4 in osteoblasts. OSM suppressed the release and the mRNA expression of OPG upregulated by BMP-4 in MC3T3-E1 cells. Neither the BMP-4-induced phosphorylation of SMAD1/5/9 nor that of p38 MAPK was affected by OSM. On the other hand, the phosphorylation of p70 S6 kinase stimulated by BMP-4 was considerably suppressed by OSM. These results strongly suggest that OSM suppresses the BMP-4-stimulated OPG synthesis via inhibition of the p70 S6 kinase-mediated pathway in osteoblast-like cells.

Oncostatin M signaling drives cancer-associated skeletal muscle wasting.

Progressive weakness and muscle loss are associated with multiple chronic conditions, including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy; however, available anticytokine therapies failed to prevent muscle wasting in cancer patients. Here, we show that oncostatin M (OSM) is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes using the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing reveals the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice causes muscle wasting, whereas muscle-specific deletion of the OSM receptor (OSMR) and the neutralization of circulating OSM preserves muscle mass and function in tumor-bearing mice. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.

Oncostatin M and STAT3 Signaling Pathways Support Human Trophoblast Differentiation by Inhibiting Inflammatory Stress in Response to IFNγ and GM-CSF.

Interleukin-6 (IL-6) superfamily cytokines play critical roles during human pregnancy by promoting trophoblast differentiation, invasion, and endocrine function, and maintaining embryo immunotolerance and protection. In contrast, the unbalanced activity of pro-inflammatory factors such as interferon gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at the maternal-fetal interface have detrimental effects on trophoblast function and differentiation. This study demonstrates how the IL-6 cytokine family member oncostatin M (OSM) and STAT3 activation regulate trophoblast fusion and endocrine function in response to pro-inflammatory stress induced by IFNγ and GM-CSF. Using human cytotrophoblast-like BeWo (CT/BW) cells, differentiated in villous syncytiotrophoblast (VST/BW) cells, we show that beta-human chorionic gonadotrophin (ßhCG) production and cell fusion process are affected in response to IFNγ or GM-CSF. However, those effects are abrogated with OSM by modulating the activation of IFNγ-STAT1 and GM-CSF-STAT5 signaling pathways. OSM stimulation enhances the expression of STAT3, the phosphorylation of STAT3 and SMAD2, and the induction of negative regulators of inflammation (e.g., IL-10 and TGFß1) and cytokine signaling (e.g., SOCS1 and SOCS3). Using STAT3-deficient VST/BW cells, we show that STAT3 expression is required for OSM to regulate the effects of IFNγ in ßhCG and E-cadherin expression. In contrast, OSM retains its modulatory effect on GM-CSF-STAT5 pathway activation even in STAT3-deficient VST/BW cells, suggesting that OSM uses STAT3-dependent and -independent mechanisms to modulate the activation of pro-inflammatory pathways IFNγ-STAT1 and GM-CSF-STAT5. Moreover, STAT3 deficiency in VST/BW cells leads to the production of both a large amount of ßhCG and an enhanced expression of activated STAT5 induced by GM-CSF, independently of OSM, suggesting a key role for STAT3 in ßhCG production and trophoblast differentiation through STAT5 modulation. In conclusion, our study describes for the first time the critical role played by OSM and STAT3 signaling pathways to preserve and regulate trophoblast biological functions during inflammatory stress.

Oncostatin M: Dual Regulator of the Skeletal and Hematopoietic Systems.

PURPOSE OF THE REVIEW: The bone and hematopoietic tissues coemerge during development and are functionally intertwined throughout mammalian life. Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family produced by osteoblasts, bone marrow macrophages, and neutrophils. OSM acts via two heterodimeric receptors comprising GP130 with either an OSM receptor (OSMR) or a leukemia inhibitory factor receptor (LIFR). OSMR is expressed on osteoblasts, mesenchymal, and endothelial cells and mice deficient for the Osm or Osmr genes have both bone and blood phenotypes illustrating the importance of OSM and OSMR in regulating these two intertwined tissues. RECENT FINDINGS: OSM regulates bone mass through signaling via OSMR, adaptor protein SHC1, and transducer STAT3 to both stimulate osteoclast formation and promote osteoblast commitment; the effect on bone formation is also supported by action through LIFR. OSM produced by macrophages is an important inducer of neurogenic heterotopic ossifications in peri-articular muscles following spinal cord injury. OSM produced by neutrophils in the bone marrow induces hematopoietic stem and progenitor cell proliferation in an indirect manner via OSMR expressed by bone marrow stromal and endothelial cells that form hematopoietic stem cell niches. OSM acts as a brake to therapeutic hematopoietic stem cell mobilization in response to G-CSF and CXCR4 antagonist plerixafor. Excessive OSM production by macrophages in the bone marrow is a key contributor to poor hematopoietic stem cell mobilization (mobilopathy) in people with diabetes. OSM and OSMR may also play important roles in the progression of several cancers. It is increasingly clear that OSM plays unique roles in regulating the maintenance and regeneration of bone, hematopoietic stem and progenitor cells, inflammation, and skeletal muscles. Dysregulated OSM production can lead to bone pathologies, defective muscle repair and formation of heterotopic ossifications in injured muscles, suboptimal mobilization of hematopoietic stem cells, exacerbated inflammatory responses, and anti-tumoral immunity. Ongoing research will establish whether neutralizing antibodies or cytokine traps may be useful to correct pathologies associated with excessive OSM production.

Oncostatin M/Oncostatin M Receptor Signal Induces Radiation-Induced Heart Fibrosis by Regulating SMAD4 in Fibroblast.

PURPOSE: Radiation-induced heart fibrosis (RIHF) is a severe consequence of radiation-induced heart damage (RIHD) leading to impaired cardiac function. The involvement of oncostatin M (OSM) and its receptor (OSMR) in RIHD remains unclear. This study aimed to investigate the specific mechanism of OSM/OSMR in RIHF/RIHD. METHODS AND MATERIALS: RNA sequencing was performed on heart tissues from a RIHD mouse model. OSM levels were assessed in serum samples obtained from patients receiving thoracic radiation therapy (RT), as well as in RIHF mouse heart tissues and serum using enzyme-linked immunosorbent assay. Fiber activation was evaluated through costimulation of primary cardiac fibroblasts and NIH3T3 cells with RT and OSM, using Western blotting, immunofluorescence, and quantitative Polymerase Chain Reaction (qPCR). Adeno-associated virus serotype 9-mediated overexpression or silencing of OSM specifically in the heart was performed in vivo to assess cardiac fibrosis levels by transthoracic echocardiography and pathologic examination. The regulatory mechanism of OSM on the transcription level of SMAD4 was further explored in vitro using mass spectrometric analysis, chromatin immunoprecipitation-qPCR, and DNA pull-down. RESULTS: OSM levels were elevated in the serum of patients after thoracic RT as well as in RIHF mouse cardiac endothelial cells and mouse serum. The OSM rate (post-RT/pre-RT) and the heart exposure dose in RT patients showed a positive correlation. Silencing OSMR in RIHF mice reduced fibrosis, while OSMR overexpression increased fibrotic responses. Furthermore, increased OSM promoted histone acetylation (H3K27ac) in the SMAD4 promoter region, influencing SMAD4 transcription and subsequently enhancing fibrotic response. CONCLUSIONS: The findings demonstrated that OSM/OSMR signaling promotes SMAD4 transcription in cardiac fibroblasts through H3K27 hyperacetylation, thereby promoting radiation-induced cardiac fibrosis and manifestations of RIHD.

Network-based cytokine inference implicates Oncostatin M as a driver of an inflammation phenotype in knee osteoarthritis.

Inflammatory cytokines released by synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine-mediated pathological communication between the synovium and cartilage. Cartilage-specific network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees displaying accelerated cartilage degradation. Next, network-based cytokine inference with pharmacological manipulation uncovered IL6 family member, Oncostatin M (OSM), as a driver of the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of OSM recapitulated an "inflammatory" phenotype of knee osteoarthritis and highlighted high-value targets for drug development and repurposing. These findings offer translational opportunities targeting the inflammation-driven osteoarthritis phenotype.

Oncostatin M suppresses IL31RA expression in dorsal root ganglia and interleukin-31-induced itching.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRß and IL31RA subunits, and OSMRß can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients. Objective: The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression. Methods: The expression levels of the OSM gene (OSM) and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes. Results: We confirmed overexpression of OSM in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed OSM upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed IL31RA expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG. Conclusion: These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch.

The clinical relevance of OSM in inflammatory diseases: a comprehensive review.

Oncostatin M (OSM) is a pleiotropic cytokine involved in a variety of inflammatory responses such as wound healing, liver regeneration, and bone remodeling. As a member of the interleukin-6 (IL-6) family of cytokines, OSM binds the shared receptor gp130, recruits either OSMRß or LIFRß, and activates a variety of signaling pathways including the JAK/STAT, MAPK, JNK, and PI3K/AKT pathways. Since its discovery in 1986, OSM has been identified as a significant contributor to a multitude of inflammatory diseases, including arthritis, inflammatory bowel disease, lung and skin disease, cardiovascular disease, and most recently, COVID-19. Additionally, OSM has also been extensively studied in the context of several cancer types including breast, cervical, ovarian, testicular, colon and gastrointestinal, brain,lung, skin, as well as other cancers. While OSM has been recognized as a significant contributor for each of these diseases, and studies have shown OSM inhibition is effective at treating or reducing symptoms, very few therapeutics have succeeded into clinical trials, and none have yet been approved by the FDA for treatment. In this review, we outline the role OSM plays in a variety of inflammatory diseases, including cancer, and outline the previous and current strategies for developing an inhibitor for OSM signaling.

A confirmed association between DNA variants in CAPN9, OSM, and ITGAM candidate genes and the risk of umbilical hernia in pigs.

Umbilical hernia (UH) is one of the most prevalent defects of swine, affecting their welfare and causing considerable economic loss. The molecular mechanisms behind UH in pigs remain poorly understood. The aim of this study was to verify the association between UH and previously reported DNA variants in the CAPN9, OSM, ITGAM, and NUGGC genes. A case/control study design was applied in two different crossbred cohorts of commercial fatteners containing 412 and 171 pigs, respectively. SNPs within CAPN9, OSM, and ITGAM were analyzed using Sanger sequencing, and 10 SNPs in CAPN9, five in OSM, and two in ITGAM were identified. A structural variant in the NUGGC gene was studied by droplet-digital PCR, and an elevated copy number was detected in only a single individual. Significant differences in allele frequencies for four SNPs in CAPN9 were detected. The haplotype analysis showed the effect on the risk of UH for two genes. The CAGGA haplotype within OSM and AT haplotype in ITGAM reduced the relative risk of UH by 52% and 45%, respectively, confirming that variants in those genes are associated with the risk of UH in pigs. Moreover, the interaction between the CAPN9 haplotype and the sex of animals had also significant impact on UH risk.

Oncostatin M regulates macrophages polarization in osseointegration via yes-associated protein.

OBJECTIVES: Oncostatin M(OSM), secreted by monocytes and macrophages, has been noted to participate in bone homeostasis and macrophage polarization, which might be regulated by yes-associated protein (YAP). This study aimed to elucidate the influence and mechanisms of OSM-YAP on macrophages polarization in osseointegration. MATERIAL AND METHODS: In vitro, flow cytometry, real-time PCR, and Elisa were performed to evaluate inflammatory function in bone marrow-derived macrophages (BMDMs) with OSM, siOSMR, and YAP inhibitor verteporfin (VP). In vivo, macrophage-specific YAP-deficient mice were generated to investigate the role of OSM via YAP signaling in osseointegration. RESULTS: This study demonstrated that OSM could inhibit the M1 polarization, promote the M2 polarization, and induce the expression of osteogenic-related factors via VP. The conditional knock-out of YAP inhibited the osseointegration in mice, and promoted the inflammatory reaction around the implants, while OSM could restore the effect. CONCLUSIONS: Our results demonstrated that OSM might play an important role in the polarization of BMDMs, and bone formation around dental and femoral implants. This effect was closely conducted by Hippo-YAP pathway. CLINICAL SIGNIFICANCE: Understanding the role and mechanism of OSM in macrophage polarization around dental implants could improve comprehension of signal network of osseointegration, and it might offer a potential target of therapies to accelerate osseointegration and reduce inflammatory reactions.

Pancreatic Stromal Cell-derived Oncostatin M Confers Drug Resistance to a Multi-tyrosine Kinase Inhibitor in Pancreatic Cancer Cells.

BACKGROUND/AIM: Pancreatic cancer is known to have one of the worst prognoses of all cancers, and its tumor cells are highly resistant to chemotherapeutic drugs. Pancreatic cancer cells coexist with stromal cells; however, their involvement in anticancer drug resistance remains poorly understood. Thus, in this study, we analyzed drug sensitivity using an in vitro co-culture system containing pancreatic cancer cells and stromal cells treated with a compound library. MATERIALS AND METHODS: We examined the viability of the pancreatic cancer cell lines BxPC-3, Capan-1, and Panc-1 against compounds in an in vitro co-culture model containing pancreatic stromal cells (PSCs) and analyzed the protein expression for drug resistance by western blotting. RESULTS: We found that co-cultured pancreatic cancer cells were resistant to vandetanib, which is an inhibitor of multi-tyrosine kinases. The key factor involved in drug resistance in these pancreatic cancer cells was oncostatin M, which was secreted by stromal cells. The addition of oncostatin M increased the vandetanib resistance of pancreatic cancer cells, while it inhibited the suppression of insulin receptor substrate-1 (IRS1) and the phosphorylation of extracellular signal-regulated kinase (ERK) by vandetanib. CONCLUSION: Oncostatin M secreted by stromal cells derived from the pancreas activates the IRS1-ERK axis, causing resistance to vandetanib.

EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia.

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer1. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength2. An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the non-canonical NFĸB pathway and was dependent on NFκB-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatin M (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatin M receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R-NIK signalling mediates cancer-associated muscle atrophy in an OSM-OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss.

Methylmercury directly modifies the 105th cysteine residue in oncostatin M to promote binding to tumor necrosis factor receptor 3 and inhibit cell growth.

We previously found that methylmercury induces expression of oncostatin M (OSM), which is released extracellularly and binds to tumor necrosis factor receptor 3 (TNFR3), possibly enhancing its own toxicity. However, the mechanism by which methylmercury causes OSM to bind to TNFR3 rather than to its known receptors, OSM receptor and LIFR, is unknown. In this study, we aimed to elucidate the effect of methylmercury modification of cysteine residues in OSM on binding to TNFR3. Immunostaining of TNFR3-V5-expressing cells suggested that methylmercury promoted binding of OSM to TNFR3 on the cell membrane. In an in vitro binding assay, OSM directly bound to the extracellular domain of TNFR3, and this binding was promoted by methylmercury. Additionally, the formation of a disulfide bond in the OSM molecule was essential for the binding of both proteins, and LC/MS analysis revealed that methylmercury directly modified the 105th cysteine residue (Cys105) in OSM. Next, mutant OSM, in which Cys105 was replaced by serine or methionine, increased the binding to TNFR3, and a similar effect was observed in immunoprecipitation using cultured cells. Furthermore, cell proliferation was inhibited by treatment with Cys105 mutant OSMs compared with wildtype OSM, and this effect was cancelled by TNFR3 knockdown. In conclusion, we revealed a novel mechanism of methylmercury toxicity, in which methylmercury directly modifies Cys105 in OSM, thereby inhibiting cell proliferation via promoting binding to TNFR3. This indicates a chemical disruption in the interaction between the ligand and the receptor is a part of methylmercury toxicity.

Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis.

Myocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulating transforming growth factor beta 1 (TGF-ß1) expression and extracellular matrix deposition. Small extracellular vesicles (SEVs) from mesenchymal stromal cells (MSCs) are being investigated to treat myocardial infarction, using different strategies to bolster their therapeutic ability. Here, we generated TERT-immortalized human MSC cell lines (MSC-T) engineered to overexpress two forms of cleavage-resistant OSM fused to CD81TM (OSM-SEVs), which allows the display of the cytokine at the surface of secreted SEVs. The therapeutic potential of OSM-SEVs was assessed in vitro using human cardiac ventricular fibroblasts (HCF-Vs) activated by TGF-ß1. Compared with control SEVs, OSM-loaded SEVs reduced proliferation in HCF-V and blunted telo-collagen expression. When injected intraperitoneally into mice treated with isoproterenol, OSM-loaded SEVs reduced fibrosis, prevented cardiac hypertrophy, and increased angiogenesis. Overall, we demonstrate that the enrichment of functional OSM on the surface of MSC-T-SEVs increases their potency in terms of anti-fibrotic and pro-angiogenic properties, which opens new perspectives for this novel biological product in cell-free-based therapies.

CD34+ cell-derived fibroblast-macrophage cross-talk drives limb ischemia recovery through the OSM-ANGPTL signaling axis.

CD34+ cells improve the perfusion and function of ischemic limbs in humans and mice. However, there is no direct evidence of the differentiation potential and functional role of these cells in the ischemic muscle microenvironment. Here, we combined the single-cell RNA sequencing and genetic lineage tracing technology, then provided exact single-cell atlases of normal and ischemic limb tissues in human and mouse, and consequently found that bone marrow (BM)-derived macrophages with antigen-presenting function migrated to the ischemic site, while resident macrophages underwent apoptosis. The macrophage oncostatin M (OSM) regulatory pathway was specifically turned on by ischemia. Simultaneously, BM CD34+-derived proregenerative fibroblasts were recruited to the ischemia niche, where they received macrophage-released OSM and promoted angiopoietin-like protein-associated angiogenesis. These findings provided mechanisms on the cellular events and cell-cell communications during tissue ischemia and regeneration and provided evidence that CD34+ cells serve as fibroblast progenitors promoting tissue regeneration.

Oncostatin M stimulates prostaglandin D2-induced osteoprotegerin and interleukin-6 synthesis in osteoblasts.

Oncostatin M produced by osteal macrophages plays a significant role in fracture healing. Osteoprotegerin (OPG) secreted by osteoblasts, binds to the receptor activator of nuclear factor-κB (RANK) ligand (RANKL) as a decoy receptor and prevents RANKL from binding to RANK, resulting in bone resorption suppression. Interleukin-6 (IL-6) is a pro-inflammatory cytokine and generally regulates bone resorption. However, accumulating evidence suggests that IL-6 plays pivotal roles in bone formation. We previously showed that prostaglandin D2 (PGD2) induces OPG synthesis by activating p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p44/p42 MAP kinase in osteoblast-like MC3T3-E1 cells. Furthermore, we demonstrated that PGD2 stimulates IL-6 synthesis by activating p38 MAP kinase and p44/p42 MAP kinase in MC3T3-E1 cells. In the present study, we investigated whether oncostatin M affects PGD2-stimulated OPG and IL-6 synthesis in MC3T3-E1 cells through MAP kinase activation. The osteoblast-like MC3T3-E1 cells and normal human osteoblasts were treated with oncostatin M and subsequently stimulated with PGD2. Consequently, oncostatin M significantly increased the PGD2-stimulated OPG and IL-6 release in both cells. Oncostatin M significantly enhanced mRNA expression levels of OPG and IL-6 induced by PGD2 similarly in both cells. Regarding the signaling mechanism, oncostatin M did not affect the phosphorylation of p38 MAP kinase, SAPK/JNK, and p44/p42 MAP kinase. Our results suggest that oncostatin M upregulates the PGD2-stimulated OPG and IL-6 synthesis in osteoblasts and therefore affects bone remodeling. However, OPG and IL-6 synthesis are not mediated through p38 MAP kinase, p44/p42 MAP kinase, or SAPK/JNK pathways.

Oncostatin M Contributes to Airway Epithelial Cell Dysfunction in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a typical type-2 inflammation involving several cytokines and is associated with epithelial cell dysfunction. Oncostatin M (OSM) (belonging to the interleukin(IL)-6 family) could be a key driver of epithelial barrier dysfunction. Therefore, we investigated the presence of OSM and IL-6 and the expression pattern of tight junctions (TJs) in the nasal tissue of CRSwNP patients and controls using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Then, their potential role in the epithelial barrier was evaluated in vitro in 27 different primary cultures of human nasal epithelial cells (HNECs) by measuring TJ expression and transepithelial electric resistance (TEER) with or without OSM or IL-6 (1, 10, and 100 ng/mL). The effect on ciliary beating efficiency was evaluated by high-speed videomicroscopy and on repair mechanisms with a wound healing model with or without OSM. OSM and IL-6 were both overexpressed, and TJ (ZO-1 and occludin) expression was decreased in the nasal polyps compared to the control mucosa. OSM (100 ng/mL) but not IL-6 induced a significant decrease in TJ expression, TEER, and ciliary beating efficiency in HNECs. After 24 h, the wound repair rate was significantly higher in OSM-stimulated HNECs at 100 ng/mL. These results suggest that OSM could become a new target for monoclonal antibodies.

Role of oncostatin-M in ECM remodeling and plaque vulnerability.

Atherosclerosis is a multifactorial inflammatory disease characterized by the development of plaque formation leading to occlusion of the vessel and hypoxia of the tissue supplied by the vessel. Chronic inflammation and altered collagen expression render stable plaque to unstable and increase plaque vulnerability. Thinned and weakened fibrous cap results in plaque rupture and formation of thrombosis and emboli formation leading to acute ischemic events such as stroke and myocardial infarction. Inflammatory mediators including TREM-1, TLRs, MMPs, and immune cells play a critical role in plaque vulnerability. Among the other inflammatory mediators, oncostatin-M (OSM), a pro-inflammatory cytokine, play an important role in the development and progression of atherosclerosis, however, the role of OSM in plaque vulnerability and extracellular matrix remodeling (ECM) is not well understood and studied. Since ECM remodeling plays an important role in atherosclerosis and plaque vulnerability, a detailed investigation on the role of OSM in ECM remodeling and plaque vulnerability is critical. This is important because the role of OSM has been discussed in the context of proliferation of vascular smooth muscle cells and regulation of cytokine expression but the role of OSM is scarcely discussed in relation to ECM remodeling and plaque vulnerability. This review focuses on critically discussing the role of OSM in ECM remodeling and plaque vulnerability.

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.