ABSTRACT
Resumo Fundamento A oncostatina M (OSM) é uma citocina pleiotrópica que, após lesão arterial, demonstra ser expressa rapidamente. Objetivos Correlacionar os níveis séricos da OSM, do receptor solúvel de oncostatina M (sOSMR) e da fração solúvel de glicoproteína 130 (sgp130) em pacientes com doença arterial coronariana (DAC) a parâmetros clínicos. Métodos Os níveis de sOSMR e sgp130 foram avaliados por ELISA, enquanto os de OSM foram avaliados por Western Blot, em pacientes com SCC (n=100), pacientes com SCA (n=70) e 64 voluntários do grupo de controle sem manifestações clínicas da doença. Valores de p <0,05 foram considerados estatisticamente significativos. Resultados Pacientes com DAC exibiram níveis significativamente mais baixos de sOSMR e sgp130 e níveis mais altos de OSM em comparação ao grupo de controle (ambos p <0,0001). A análise clínica mostrou níveis mais baixos de sOSMR em homens ([OR] = 2,05, p = 0,026), jovens (OR = 1,68, p = 0,0272), hipertensos (OR = 2,19, p = 0,041), fumantes (OR = 2,19, p = 0,017), pacientes que não apresentavam dislipidemia (OR = 2,32, p = 0,013), pacientes com infarto agudo do miocárdio [IAM] (OR = 3,01, p = 0,001) e pacientes não tratados com estatina (OR = 1,95, p = 0,031), antiplaquetário (OR = 2,46, p = 0,005), inibidores dos canais de cálcio (OR = 3,15, p = 0,028) e antidiabéticos (OR = 2,97, p = 0,005). Os níveis de sOSMR também foram correlacionados a sexo, idade, hipertensão e uso de medicamentos na análise multivariada. Conclusões Nossos dados sugerem que o aumento dos níveis séricos de OSM e a diminuição dos níveis de sOSMR e sGP130 em pacientes com injúria cardíaca podem desempenhar um papel importante no mecanismo fisiopatológico da doença. Além disso, níveis mais baixos de sOSMR foram associados a sexo, idade, hipertensão e uso de medicamentos.
Abstract Background Oncostatin M (OSM) is a pleiotropic cytokine which, after arterial injury, has proven to be to be rapidly expressed. Objectives To correlate the serum levels of OSM, soluble OSM receptor (sOSMR), and soluble fraction of glycoprotein 130 (sgp130) in patients with coronary artery disease (CAD) with clinical parameters. Methods Levels of sOSMR and sgp130 were evaluated by ELISA and OSM by Western Blot, in patients with CCS (n=100), patients with ACS (n=70), and 64 control volunteers without clinical manifestations of the disease. P-values < 0.05 were considered to be statistically significant. Results CAD patients exhibited significantly lower levels of sOSMR and sgp130 and higher levels of OSM when compared to the controls (both p < 0.0001). Clinical analysis displayed, lower levels of sOSMR in men ([OR] = 2.05, p = 0.026), youth (OR = 1.68, p = 0.0272), hypertensives (OR = 2.19, p = 0.041), smokers (OR = 2.19, p = 0.017), patients that did not present dyslipidemia (OR = 2.32, p = 0.013), patients with Acute Myocardial Infarction [AMI] (OR = 3.01, p = 0.001) and patients not treated with statin (OR = 1.95, p = 0.031), antiplatelet agent (OR = 2.46, p = 0.005), inhibitors of calcium channels (OR = 3.15, p = 0.028), and antidiabetic drugs (OR = 2.97, p = 0.005). The levels of sOSMR were also correlated with gender, age, hypertension, and use of medications in multivariate analysis. Conclusions Our data suggest that the enhanced serum levels of OSM, and decreased levels of sOSMR and sGP130 in patients with cardiac injury may play an important role in the pathophysiological mechanism of the disease. Furthermore, lower levels of sOSMR were associated with gender, age, hypertension, and the use of medications.
ABSTRACT
ABSTRACT 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.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Insulin Resistance/physiology , Oncostatin M/blood , Inflammation/blood , Case-Control Studies , Pilot Projects , Chronic Disease , Cross-Sectional Studies , Prospective StudiesABSTRACT
PURPOSE: To investigate the effect of oncostatin M (OSM) on protein expression levels and enzymatic activities of matrix metalloprotainase (MMP)-2 and MMP-9 in primary trophoblasts and the invasiveness thereof under normoxia and hypoxia conditions. MATERIALS AND METHODS: Protein expression levels and enzymatic activities of MMP-2 and MMP-9 in primary trophoblasts under normoxia and hypoxia conditions were examined by Western blot and zymography, respectively. Effects of exogenous OSM on the in vitro invasion activity of trophoblasts according to oxygen concentration were also determined. Signal transducer and activator of transcription 3 (STAT3) siRNA was used to determine whether STAT3 activation in primary trophoblasts was involved in the effect of OSM. RESULTS: OSM enhanced protein expression levels and enzymatic activities of MMP-2 and MMP-9 in term trophoblasts under hypoxia condition, compared to normoxia control (p < 0.05). OSM-induced MMP-2 and MMP-9 enzymatic activities were significantly suppressed by STAT3 siRNA silencing under normoxia and hypoxia conditions (p < 0.05). Hypoxia alone or OSM alone did not significantly increase the invasiveness of term trophoblasts. However, the invasion activity of term trophoblasts was significantly increased by OSM under hypoxia, compared to that without OSM treatment under normoxia. CONCLUSION: OSM might be involved in the invasiveness of extravillous trophoblasts under hypoxia conditions via increasing MMP-2 and MMP-9 enzymatic activities through STAT3 signaling. Increased MMP-9 activity by OSM seems to be more important in primary trophoblasts.
Subject(s)
Hypoxia , Blotting, Western , In Vitro Techniques , Oncostatin M , Oxygen , RNA, Small Interfering , STAT3 Transcription Factor , TrophoblastsABSTRACT
Objective To investigate the effects of oncostatin M(OSM) on differentiation of murine induced pluri-potent stem cells(miPSCs) into cardiomyocytes in vitro. Methods Using the embryoid bodies differentiation meth-od,OSM was added during early-phase and midphase(day 0-6) of miPSCs differentiation for 15 days.Semi-quan-titative RT-PCR,Western blot and immunofluorescence staining were used to detect the expression levels of myo-cardial cells-specific markers. Results The best concentration of OSM to induce the cardiac differentiation of miP-SCs was 20 pmol/L and cardiac troponin-T(cTnT) was expressed 7-fold higher in OSM-treated compared with vehi-cle control-treated embryoid bodies at day 15 post-differentiation. Cardiac-specific gene and protein expression of cTnT and Gata4 demonstrated that the OSM-treated embryoid bodies expressed cardiac-specific gene(Tnnt2, Nkx2.5,MLC2a,MLC2v,GATA4 and GATA6) and protein (cTnI,Gata4) at levels that were higher than those of the vehicle-control group after induced for 15 days. Furthermore, Immunostaining of the cardiac-specific protein markers cTnT showed that the miPSCs expressed cTnT across all groups, and exhibited a markedly increased of cTnT-positive cells in OSM-treated cells. Conclusions OSM promotes the differentiation of murine induced pluripo-tent stem cells into cardiomyocytes, and it could serve as a valuable strategy for myocardiac differentiation of miPSCs in vitro.
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Objective To investigate the effects of oncostatin M(OSM) on differentiation of murine induced pluri-potent stem cells(miPSCs) into cardiomyocytes in vitro. Methods Using the embryoid bodies differentiation meth-od,OSM was added during early-phase and midphase(day 0-6) of miPSCs differentiation for 15 days.Semi-quan-titative RT-PCR,Western blot and immunofluorescence staining were used to detect the expression levels of myo-cardial cells-specific markers. Results The best concentration of OSM to induce the cardiac differentiation of miP-SCs was 20 pmol/L and cardiac troponin-T(cTnT) was expressed 7-fold higher in OSM-treated compared with vehi-cle control-treated embryoid bodies at day 15 post-differentiation. Cardiac-specific gene and protein expression of cTnT and Gata4 demonstrated that the OSM-treated embryoid bodies expressed cardiac-specific gene(Tnnt2, Nkx2.5,MLC2a,MLC2v,GATA4 and GATA6) and protein (cTnI,Gata4) at levels that were higher than those of the vehicle-control group after induced for 15 days. Furthermore, Immunostaining of the cardiac-specific protein markers cTnT showed that the miPSCs expressed cTnT across all groups, and exhibited a markedly increased of cTnT-positive cells in OSM-treated cells. Conclusions OSM promotes the differentiation of murine induced pluripo-tent stem cells into cardiomyocytes, and it could serve as a valuable strategy for myocardiac differentiation of miPSCs in vitro.
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PURPOSE: Our previous studies have shown that oncostatin M (OSM) promotes trophoblast invasion activity through increased enzyme activity of matrix metalloproteinase (MMP)-2 and -9. We further investigated OSM-induced intracellular signaling mechanisms associated with these events in the immortalized human trophoblast cell line HTR8/SVneo. MATERIALS AND METHODS: We investigated the effects of OSM on RNA and protein expression of MMP-2 and -9 in the first-trimester extravillous trophoblast cell line (HTR8/SVneo) via Western blot. The selective signal transducer and activator of transcription (STAT)3 inhibitor, stattic, STAT3 siRNA, and extracellular signal-regulated kinase (ERK) siRNA were used to investigate STAT3 and ERK activation by OSM. The effects of STAT3 and ERK inhibitors on OSM-induced enzymatic activities of MMP-2 and -9 and invasion activity were further determined via Western blot and gelatin zymography. RESULTS: OSM-induced MMP-2 and -9 protein expression was significantly suppressed by STAT3 inhibition with stattic and STAT3 siRNA silencing, whereas the ERK1/2 inhibitor (U0126) and ERK silencing significantly suppressed OSM-induced MMP-2 protein expression. OSM-induced MMP-2 and MMP-9 enzymatic activities were significantly decreased by stattic pretreatment. The increased invasion activity induced by OSM was significantly suppressed by STAT3 and ERK1/2 inhibition, though to a greater extent by STAT3 inhibition. CONCLUSION: Both STAT3 and ERK signaling pathways are involved in OSM-induced invasion activity of HTR8/SVneo cells. Activation of STAT3 appears to be critical for the OSM-mediated increase in invasiveness of HTR8/SVneo cells.
Subject(s)
Humans , Blotting, Western , Cell Movement/drug effects , Cell Proliferation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 9/genetics , Oncostatin M/genetics , Phosphorylation/drug effects , RNA, Messenger/metabolism , RNA, Small Interfering , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effectsABSTRACT
Objective:To observe and identify the inhibitory effect of oncostatin M (OSM) combined with dacarbazine (DTIC) on mouse melanoma cells B16 in vitro and in vivo. Methods:The inhibitory effect of OSM combined with DTIC on the proliferation and apoptosis of B16 melanoma cell line B16 were determined through MTT assay and flow cytometry, respectively. The change in nu-cleus morphology of B16 cells was observed under a fluorescence microscope by Hoechst staining method. The effects of single agents OSM and DTIC, as well as OSM-DTIC joint treatments, on tumor in mice in vivo were observed by inoculating B16 cells into C57 BL of six mice. Results:The OSM, DTIC, and combined OSM-DTIC treatments inhibited the proliferation of B16 cells by (11.2±2.3)%, (25.3±4.6)%, and (32.5±3.8)%, respectively (P<0.05). Apoptosis of B16 occurred at (1.32±0.42)%, (10.64±2.13)%, and (15.86±2.76)%, respectively (P<0.05). Cell morphology showed a significant increase in nuclear fragmentation, as proven by OSM-DTIC combined treatment. In the in vivo experiment, DTIC caused an apparent inhibition on the growth of mouse melanoma compared with the control group, and the joint treatment showed that the addition of OSM enhanced the tumor suppression effect of DTIC. Conclusion: OSM combined with DTIC has a synergistic effect that inhibits proliferation and apoptosis of B16 in vitro. This approach suggests a new po-tential treatment for melanoma.
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OBJECTIVES: To investigate the association between papillary thyroid cancer (PTC) and single nucleotide polymorphisms (SNPs) of oncostatin M receptor (OSMR) in the Korean population. METHODS: Retrospective case-control study was done. Eighty-five patients with PTC and 287 controls were studied. One missense SNP (rs2278329, Asp553Asn) and one promoter SNP (rs2292016, -100 G/T) of the OSMR gene were genotyped by direct sequencing. Genetic data were analyzed using the SNPStats, Helixtree, and SNPAnalyzer Pro. PTC patients were dichotomized and compared with respect to the clinicopathologic characteristics. RESULTS: There was no association between genotypes and allele frequencies of OSMR SNPs (rs2278329 and rs2292016) and PTC susceptibility. SNP rs2278329 was significantly associated with tumor size (dominant model; P=0.028; odds ratio [OR], 2.71; 95% confidence interval [CI], 1.12 to 6.57). The A allele was higher in sizes large than 1 cm (32.5% vs. 16.7%; P=0.018; OR, 2.41; 95% CI, 1.17 to 4.98). Regarding the number of tumors, we found no significant association with genotype, however, the A allele was higher in patients with multifocaltiy (33.3% vs. 19.1%; P=0.040; OR, 2.12; 95% CI, 1.03 to 4.34). CONCLUSION: The results suggest that OSMR polymorphism rs2278329 is associated with clinicopathologic characteristics of the tumor growth and multifocality development.
Subject(s)
Humans , Alleles , Case-Control Studies , Factor IX , Gene Frequency , Genotype , Odds Ratio , Oncostatin M , Polymorphism, Single Nucleotide , Receptors, Oncostatin M , Retrospective Studies , Thyroid Gland , Thyroid NeoplasmsABSTRACT
PURPOSE: Oncostatin M(OSM) is a multifunctional cytokine that belongs to the interleukin(IL)-6 family. Although there have been a number of studies that focused on the role and mechanism of OSM in various organs and tissues, there are few reports on its effect on wound healing. The final purpose of this project is to evaluate the effect of OSM on wound healing. This pilot study was designed to investigate the effect of OSM on proliferation and matrix synthesis of human dermal fibroblasts, which are the major components of the wound healing. METHODS: Excess skin that was obtained from patients who underwent skin grafts, was used for this study. From this material, fibroblasts were isolated and cultured. The cultured fibroblasts were treated with one of four concentrations of OSM. The OSM concentrations used were 0, 50, 100, and 200ng/ml, respectively. After the OSM treatment, cell proliferation was determined by the MTT assay, collagen synthesis by the C1CP method, GAG levels by the Blyscan Dye method. The parameter levels of each group were compared. RESULTS: OSM treatment increased all the components tested in the study. In particular, cell proliferation, GAG synthesis demonstrated statistically significant increases(p<0.05 in the Mann-Whitney U-test). The highest increase in all the components was obtained at a 100ng/ml concentration of OSM. CONCLUSION: The results of the present study indicate that OSM stimulates proliferation and matrix synthesis of human dermal fibroblast and the optimal concentration for wound healing is 100ng/mL.
Subject(s)
Humans , Cell Proliferation , Collagen , Fibroblasts , Oncostatin M , Pilot Projects , Skin , Transplants , Wound HealingABSTRACT
PURPOSE: Oncostatin M(OSM) has been known as a role in fibrosis and anti-inflammatory effects of various organs and tissues. Although there have been a number of studies which are focused on the roles and mechanisms of OSM, there are few reports on its effects in chronic wound healing. The purpose of this study is to evaluate the effects of OSM in wound healing activities of dermal fibroblasts of chronic wound in vitro. In particular, this study is focused on cell proliferation and synthesis of collagen and glycosaminoglycan(GAG), which are the major components of the extracellular matrices, of diabetic fibroblasts. METHODS: Fibroblasts were isolated from excess skin that was obtained from diabetic foot ulcer patients who underwent debridement. The isolated fibroblasts were cultivated in presence of OSM(100ng/mL). Cell proliferation, collagen synthesis and GAG levels were compared. RESULTS: All the components tested in this study increased in OSM treatment group. In particular, collagen and GAG synthesis demonstrated statistically significant increases(p<0.05 in the Mann-Whitney U- test). CONCLUSION: These results indicate that OSM increases wound healing activities of dermal fibroblasts of chronic wound in vitro.
Subject(s)
Humans , Cell Proliferation , Collagen , Debridement , Diabetic Foot , Extracellular Matrix , Fibroblasts , Fibrosis , Oncostatin M , Skin , Ulcer , Wound HealingABSTRACT
It has become increasingly clear that cytokines play an important role in modulating neuroendocrine regulation, especially in the secretion of corticotropin (ACTH) in the pituitary. Oncostatin M (OSM), a cytokine of IL-6 family has been reported to increase ACTH secretion and pro-opiomelanocortin (POMC) transcription in murine corticotroph pituitary tumor cells (AtT20 cells). The present study was undertaken to determine the effects of OSM on hormonal release in primary culture of rat pituitary cells. Growth hormone or prolactin release was not affected by OSM. OSM (1 nM) stimulated ACTH release (35.1% increase versus control, p>0.001) in dispersed pituitary cells of rat to a lesser extent than in AtT20 cells. Corticotropin releasing hormone (CRH) (10 nM) also induced a 2.3-fold increase of ACTH secretion (p>0.001), but co-treatment of OSM and CRH did not exhibit any synergistic effect on ACTH secretion. We conclude OSM has a stimulatory effect on ACTH secretion in normal rat pituitary cell cultures, and OSM acts mainly on corticotroph, supporting the potential role of OSM to modulate immune-endocrine regulation in the pituitary.
Subject(s)
Male , Rats , Animals , Cells, Cultured , Adrenocorticotropic Hormone/metabolism , Cytokines/pharmacology , Cytokines/metabolism , Inflammation Mediators/pharmacology , Inflammation Mediators/metabolism , Peptides/pharmacology , Peptides/metabolism , Pituitary Gland/metabolism , Pituitary Gland/drug effects , Pituitary Gland/cytology , Prolactin/metabolism , Rats, Inbred WF , Growth Hormone/metabolismABSTRACT
It has become increasingly clear that cytokines play an important role in modulating neuroendocrine regulation, especially in the secretion of corticotropin (ACTH) in the pituitary. Oncostatin M (OSM), a cytokine of IL-6 family has been reported to increase ACTH secretion and pro-opiomelanocortin (POMC) transcription in murine corticotroph pituitary tumor cells (AtT20 cells). The present study was undertaken to determine the effects of OSM on hormonal release in primary culture of rat pituitary cells. Growth hormone or prolactin release was not affected by OSM. OSM (1 nM) stimulated ACTH release (35.1% increase versus control, p>0.001) in dispersed pituitary cells of rat to a lesser extent than in AtT20 cells. Corticotropin releasing hormone (CRH) (10 nM) also induced a 2.3-fold increase of ACTH secretion (p>0.001), but co-treatment of OSM and CRH did not exhibit any synergistic effect on ACTH secretion. We conclude OSM has a stimulatory effect on ACTH secretion in normal rat pituitary cell cultures, and OSM acts mainly on corticotroph, supporting the potential role of OSM to modulate immune-endocrine regulation in the pituitary.