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Cells Feb 2021Pro-inflammatory cytokines are considered to play a major role in osteoarthritis (OA), yet so far, the specific cytokines involved in the pathology of OA have not been...
Pro-inflammatory cytokines are considered to play a major role in osteoarthritis (OA), yet so far, the specific cytokines involved in the pathology of OA have not been identified. Oncostatin M (OSM) is a cytokine from the interleukin 6 (IL-6) family that has been shown to be elevated in synovial fluid of most rheumatoid arthritis (RA) patients, but only in a limited subset of OA patients. Little is known about OSM in the different joint tissues during OA and how its expression correlates with hallmarks of disease. Here, we mapped OSM expression in the joint tissues of two rat models of arthritis: an acute inflammatory model and an instability-induced osteoarthritic model. OSM expression was correlated with hallmarks of OA, namely cartilage damage, synovitis, and osteophyte formation. Reanalysis of an existing dataset on cytokine profiling of OA synovial fluid was performed to assess pattern differences between patients positive and negative for OSM. In the inflammatory model, OSM expression correlated with synovitis and osteophyte formation but not with cartilage damage. On the contrary, in the instability model of OA, an increase in synovitis, cartilage damage, and osteophyte formation was observed without changes in OSM expression. In line with these findings, synovial fluid of OA patients with detectable OSM contained higher levels of other inflammatory cytokines, namely interferon gamma (IFN-γ), IL-1α and tumor necrosis factor alpha (TNF-α), likely indicating a more inflammatory state. Taken together these data indicate OSM might play a prominent role in inflammatory phenotypes of OA.
Topics: Animals; Antineoplastic Agents; Arthritis, Experimental; Disease Models, Animal; Female; Humans; Inflammation; Male; Oncostatin M; Osteoarthritis; Phenotype; Rats
PubMed: 33673583
DOI: 10.3390/cells10030508 -
Journal of Cellular and Molecular... Jan 2019Oncostatin M (OSM) is a pleiotropic cytokine within the interleukin six family of cytokines, which regulate cell growth and differentiation in a wide variety of...
Oncostatin M (OSM) is a pleiotropic cytokine within the interleukin six family of cytokines, which regulate cell growth and differentiation in a wide variety of biological systems. However, its action and underlying mechanisms on stem Leydig cell development are unclear. The objective of the present study was to investigate whether OSM affects the proliferation and differentiation of rat stem Leydig cells. We used a Leydig cell regeneration model in rat testis and a unique seminiferous tubule culture system after ethane dimethane sulfonate (EDS) treatment to assess the ability of OSM in the regulation of proliferation and differentiation of rat stem Leydig cells. Intratesticular injection of OSM (10 and 100 ng/testis) from post-EDS day 14 to 28 blocked the regeneration of Leydig cells by reducing serum testosterone levels without affecting serum luteinizing hormone and follicle-stimulating hormone levels. It also decreased the levels of Leydig cell-specific mRNAs (Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1 and Hsd11b1) and their proteins by the RNA-Seq and Western blotting analysis. OSM had no effect on the proliferative capacity of Leydig cells in vivo. In the seminiferous tubule culture system, OSM (0.1, 1, 10 and 100 ng/mL) inhibited the differentiation of stem Leydig cells by reducing medium testosterone levels and downregulating the expression of Leydig cell-specific genes (Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1 and Hsd11b1) and their proteins. OSM-mediated action was reversed by S3I-201 (a STAT3 antagonist) or filgotinib (a JAK1 inhibitor). These data suggest that OSM is an inhibitory factor of rat stem Leydig cell development.
Topics: Animals; Cell Differentiation; Cell Proliferation; Down-Regulation; Follicle Stimulating Hormone; Leydig Cells; Luteinizing Hormone; Male; Oncostatin M; RNA, Messenger; Rats; Rats, Sprague-Dawley; Regeneration; Stem Cells; Testis; Testosterone
PubMed: 30320465
DOI: 10.1111/jcmm.13946 -
Cancer Research Oct 2021Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC), and its progression has been linked to chronic inflammation. About...
Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC), and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel-Lindau () tumor-suppressor gene. However, it is still not clear how mutations in , encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor-α (HIFα), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells. Interestingly, the endothelial cells (EC), although not subject to genetic manipulation, nonetheless showed profound changes in gene expression that suggest a role in promoting inflammation and tumorigenesis. Oncostatin M (OSM) mediated the interaction between -deficient renal tubule cells and the ECs, and the activated ECs in turn induced macrophage recruitment and polarization. The OSM-dependent microenvironment also promoted metastasis of exogenous tumors. Thus, OSM signaling initiates reconstitution of an inflammatory and tumorigenic microenvironment by -deficient renal tubule cells, which plays a critical role in ccRCC initiation and progression. SIGNIFICANCE: A novel mechanism of cross-talk between ECs and -deficient kidney tubules that stimulates inflammation and tumorigenesis is discovered, suggesting OSM could be a potential target for ccRCC intervention.
Topics: Animals; Cell Line; Cell Transformation, Neoplastic; Cellular Reprogramming; Disease Models, Animal; Disease Susceptibility; Endothelial Cells; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Humans; Immunohistochemistry; Kidney Neoplasms; Macrophages; Mice; Mice, Transgenic; Mutation; Oncostatin M; Phenotype; Signal Transduction; Tumor Microenvironment; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 34301760
DOI: 10.1158/0008-5472.CAN-21-0345 -
International Journal of Molecular... Jun 2022Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with inflammation and tissue remodeling including myofibroblasts differentiation and extracellular matrix...
Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with inflammation and tissue remodeling including myofibroblasts differentiation and extracellular matrix (ECM) deposition mediated by TGF-β1 and IL-4. Oncostatin M (OSM) is a cytokine involved in fibrotic processes in other cellular subtypes. We investigated the mechanisms of action of OSM in the fibrosis process associated with CRSwNP. The expression of IL-4, OSM and TGF-β1 was assessed by RT-qPCR. Primary human cultures of nasal-polyp-derived fibroblasts were established and stimulated by TGF-β1 and/or IL-4 and/or OSM. The expression of ECM components and αSMA was determined by RT-qPCR and Western blot. TGF-β1-Smad3 signaling was investigated by immunofluorescence. TGF-β1, IL-4 and OSM as well as αSMA were overexpressed in nasal polyps when compared to noninflammatory nasal mucosa. In TGF-β1-stimulated nasal-polyp-derived fibroblasts, ECM genes and αSMA gene and protein were overexpressed, as well as αSMA in IL-4-stimulated fibroblasts. OSM counteracted the profibrotic effect of TGF-β1 on ECM components and αSMA. TGF-β1-induced nuclear translocation of Smad3 was completely reversed by OSM. OSM counteracts the profibrotic effect of IL-4 and also TGF-β1, by inhibiting the nuclear translocation of Smad3. We suggest OSM could be an efficient tool to protect against fibrosis in CRSwNP.
Topics: Cells, Cultured; Fibroblasts; Fibrosis; Humans; Interleukin-4; Nasal Polyps; Oncostatin M; Sinusitis; Transforming Growth Factor beta1
PubMed: 35682987
DOI: 10.3390/ijms23116308 -
Arthritis and Rheumatism Dec 2003
Review
Topics: Animals; Arthritis; Humans; Oncostatin M; Peptides
PubMed: 14673980
DOI: 10.1002/art.11348 -
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 -
Cancer Letters Oct 2021Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis...
Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis and HCC patients; however, its role in hepatocarcinogenesis has not been clearly elucidated. In this study, we investigated the effect of OSM on HCC occurrence in a rat model of N-diethylnitrosamine-induced HCC. OSM overexpression significantly increased the number of tumor nodules and shortened the overall survival of the rats. Notably, OSM promoted HPC activation in vivo but did not directly regulate the proliferation of the HPC cell line in vitro. Further, OSM induced tumor necrosis factor-α (TNF-α) secretion and CD68 macrophage accumulation, which were positively correlated with HPC activation. Additionally, TNF-α or macrophage depletion inhibited the promoting effect of OSM on hepatocarcinogenesis and HPC activation. Furthermore, OSM expression in the peritumoral tissues of HCC was positively correlated with poor overall survival of patients. In conclusion, OSM plays an important role in hepatocarcinogenesis by regulating the liver inflammation environment. Hence, OSM could be used as a potential target for HCC prevention and therapy or as an indicator of HCC prognosis.
Topics: Adult; Aged; Animals; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line; Cell Proliferation; Female; Humans; Liver; Liver Neoplasms; Macrophages; Male; Middle Aged; Oncostatin M; Prognosis; Rats; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 34102284
DOI: 10.1016/j.canlet.2021.05.039 -
International Journal of Molecular... Apr 2021Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata...
Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68, CD163 and CD206 macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.
Topics: Adult; Apoptosis; Aurora Kinases; Cardiomyopathies; Cell Proliferation; Cytoskeletal Proteins; Female; Granuloma; Histones; Humans; Ki-67 Antigen; Macrophages; Male; Membrane Proteins; Microfilament Proteins; Middle Aged; Myocardium; Oncostatin M; Pancreatitis-Associated Proteins; Sarcoidosis
PubMed: 33923774
DOI: 10.3390/ijms22084148 -
Andrology Feb 2022Oncostatin M (OSM) is a member of the interleukin-6 group of cytokines, which can regulate cell proliferation, growth, and function. Immature Leydig cells have the...
Oncostatin M stimulates immature Leydig cell proliferation but inhibits its maturation and function in rats through JAK1/STAT3 signaling and induction of oxidative stress in vitro.
BACKGROUND
Oncostatin M (OSM) is a member of the interleukin-6 group of cytokines, which can regulate cell proliferation, growth, and function. Immature Leydig cells have the ability to proliferate and differentiate, and adult Leydig cells have the function of testosterone synthesis. However, the role and underlying mechanisms of OSM on the proliferation and function of Leydig cells remain unclear.
METHODS
The effects of OSM on the proliferation, apoptosis, and function of immature Leydig cells isolated from 35-day-old rats and the function of adult Leydig cells isolated from 63-day-old rats in vitro.
RESULTS
OSM stimulated immature Leydig cell proliferation after up-regulating the expression of Ccnd1 and Cdk4 to drive the transition of G1 phase to M2 phase in the cell cycle at 10 and 100 ng/ml. OSM did not affect the apoptosis of immature Leydig cells up to 100 ng/ml. OSM inhibited testosterone production in immature and adult Leydig cells by down-regulating the expression of Lhcgr, Star, Cyp11a1, Hsd3b1, and Cyp17a1 at 1-100 ng/ml. OSM induced reactive oxygen species and down-regulated the expression of antioxidant genes and lowered mitochondrial membrane potential at 10 and 100 ng/ml in both Leydig cells. Janus kinase 1 (JAK1) antagonist filgotinib and signal transducer and activator of transcription 3 (STAT3) antagonist S3I-201 reversed the effect of OSM, indicating that it acts on JAK1/STAT3 signaling.
CONCLUSION
Oncostatin M stimulates immature Leydig cell proliferation while inhibiting the function of immature and adult Leydig cells.
Topics: Animals; Cell Proliferation; Janus Kinase 1; Leydig Cells; Male; Oncostatin M; Oxidative Stress; Rats; STAT3 Transcription Factor; Signal Transduction
PubMed: 34516050
DOI: 10.1111/andr.13109 -
Biomedical Research (Tokyo, Japan) 2022Bone fracture is an important trauma frequently encountered into emergency medicine as well as orthopedics reflecting an aging society. Oncostatin M, an inflammatory...
Bone fracture is an important trauma frequently encountered into emergency medicine as well as orthopedics reflecting an aging society. Oncostatin M, an inflammatory cytokine produced by osteal macrophages, has been considered to play a crucial role in fracture healing. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts is essential in osteoclastgenesis, and the secretion is stimulated by transforming growth factor-β (TGF-β). The aim of this study is to elucidate the effects of oncostatin M on the TGF-β-induced M-CSF synthesis in osteoblast-like MC3T3-E1 cells and the underlying mechanisms. Oncostatin M attenuated the TGF-β-stimulated M-CSF release and the mRNA expressions. SMAD3 inhibitor SIS3, p38 MAP kinase inhibitor SB203580, MEK1/2 inhibitor PD98059, and SAPK/JNK inhibitor SP600125 significantly suppressed the M-CSF release. Oncostatin M suppressed the TGF-β-induced phosphorylation of p44/p42 MAP kinase and SAPK/JNK, but failed to affect the phosphorylation of SMAD3 and p38 MAP kinase. Oncostatin M attenuated the TGF-β-stimulated vascular endothelial growth factor (VEGF) release and the TGF-β-induced mRNA expressions of VEGF. These results strongly suggest that oncostatin M downregulates TGF-β signaling upstream of p44/p42 MAP kinase and SAPK/JNK, but not SMAD 2/3 and p38 MAP kinase, in osteoblasts, leading to the attenuation of M-CSF synthesis. Our findings might provide a new therapeutic strategy for the acceleration of fracture healing process.
Topics: Macrophage Colony-Stimulating Factor; Macrophages; Mitogen-Activated Protein Kinase 1; Oncostatin M; Osteoblasts; Phosphorylation; RNA, Messenger; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; p38 Mitogen-Activated Protein Kinases
PubMed: 35431291
DOI: 10.2220/biomedres.43.41