Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice

Nakamura, Koji; Nonaka, Hiroshi; Saito, Hiroki; Tanaka, Minoru; Miyajima, Atsushi

doi:10.1002/hep.20086

Cited by 140 publications

(125 citation statements)

References 51 publications

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“…It is likely that the infiltrating macrophages or neutrophils secrete OSM that in turn functions to recruit additional inflammatory cells into the injured muscles and to prevent premature differentiation of myoblasts [32]. In addition to a direct effect on myoblasts shown in this report, OSM may also contribute to muscle regeneration by regulating muscle stem cell niche, as OSM/ OSMR is known to regulate the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases [69][70][71]. The balanced action of these two classes of proteins regulates the integrity of extracellular matrix and is essential during tissue remodeling and repair.…”

Section: The Role Of Osm In the Early Phase Of The Injury-induced Musmentioning

confidence: 68%

Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration

Xiao

Wang

et al. 2010

Cell Res

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Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays important roles during inflammation. However, its roles in myoblast differentiation and muscle regeneration remain unexplored. We show here that OSM potently inhibited myoblast differentiation mainly by activating the JAK1/STAT1/STAT3 pathway. OSM downregulated myocyte enhancer-binding factor 2A (MEF2A), upregulated the expression of Id1 and Id2, and inhibited the transcriptional activity of MyoD and MEF2. In addition, OSM also enhanced the expression of STAT3 and OSM receptor, which constituted a positive feedback loop to further amplify OSM-induced signaling. Moreover, we found that STAT1 physically associated with MEF2 and repressed its transcriptional activity, which could account for the OSM-mediated repression of MEF2. Although undetectable in normal muscles in vivo, OSM was rapidly induced on muscle injury and then promptly downregulated just before the majority of myoblasts differentiate. Prolonged expression of OSM in muscles compromised the regeneration process without affecting myoblast proliferation, suggesting that OSM functions to prevent proliferating myoblasts from premature differentiation during the early phase of muscle regeneration.

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Section: The Role Of Osm In the Early Phase Of The Injury-induced Musmentioning

confidence: 68%

Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration

Xiao

Wang

et al. 2010

Cell Res

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“…The first goal of this study was to establish the signaling specificity of IL-31 and OSM, two cytokines predicted to be relevant for regulating epithelial cells (8,15,22,23,35). Assessment of signaling specificity was in part prompted by the prediction that the receptors for these two cytokines, like the other members of the IL-6 cytokine receptors, exert redundant functions due to shared receptor subunits (25).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-31 and Oncostatin-M Mediate Distinct Signaling Reactions and Response Patterns in Lung Epithelial Cells

Chattopadhyay

Tracy

Liang

et al. 2007

Journal of Biological Chemistry

121

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Many mammalian cell types co-express several receptors for the evolutionarily related hematopoietic cytokines of the interleukin (IL) 4 -6 group (1). Moreover, all cell types express gp130, the common signal-transducing subunit of this receptor family. A major unresolved issue is whether the receptors for the individual IL-6 cytokines exert redundant functions because of the involvement of shared subunits, or whether they exert specific actions because of the formation of heteromeric subunit combinations. Gross analyses of cell responses to IL-6 cytokines indicated similar signaling reactions, supporting the notion of redundancy (2, 3). However, the individual receptor forms determine not only the ability of the cells to respond to specific IL-6 cytokines by mediating ligand binding but also the quantitative signaling by the relative expression levels of receptor subunits (4). The model of IL-6 cytokine receptors directing specific action takes into consideration that receptor complexes engage cytoplasmic domains of two signal-transducing subunits with distinct structures and capabilities to communicate to signaling pathways (3, 5). The ligand-dependent association of receptor subunits into signaling-competent complexes leads invariably to the activation of JAKs and to a specific pattern of auto-and trans-tyrosine phosphorylation of kinases, receptor subunits, and interacting proteins, including STATs, Src homology 2-containing phosphatase 2, Src homology 2-containing protein C (SHC) and other adaptor proteins. The receptor proximal events at the plasma membrane and the level of sustained signaling defines the duration and magnitude of cell responses, including transcriptional induction of genes, altered cell morphology, and changes in cell proliferation. Proliferation control by cytokine-activated STAT proteins has gained particular attention in part to explain the role of IL-6 cytokines in tissue damage repair (6 -8) and potential relevance to support tumorigenesis (9, 10). Unexplained thus far is the basis for the divergent outcome of IL-6 cytokine action that, in certain epithelial cell types, yields a suppression of proliferation (11), whereas in other cell types it yields a growth promotion (12, 13). Because the subunits for IL-6 cytokine receptors are encoded by single-copy genes, comparable structures and biochemical actions are expected for the receptor proteins expressed in the various cell types, regardless of the ultimate outcome of cytokine treatment.An independent assessment of receptor signaling specificity among IL-6 cytokine receptors became possible with the identification of IL-31R␣ (gp130-like protein; see Ref. 14) as a member of the IL-6R group that does not engage gp130, but OSMR␤, to form a signaling receptor complex (15,16). Based on the effects of ectopic expression in transgenic mice, IL-31, a CD4 ϩ T-cell-derived cytokine, has been associated with pruritis and dermatitis affecting dermal keratinocytes and dorsal root ganglia (17-19). Because antigenic challenge increased levels of * Th...

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“…They have also shown that the administration of OSM reduces CCl 4 -induced acute liver failure in wildtype mice. 21 These results suggest that OSM, like HGF, plays an important role in liver regeneration.Recently, we have succeeded in isolating rat OSM cDNA. 22 In this study, we examined whether the introduction of this OSM cDNA enhances liver regeneration and suppresses fibrogenesis in rats administrated with dimethylnitrosamine (DMN).…”

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confidence: 84%

mentioning

confidence: 84%

Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

Hamada

Sato

Hirano

et al. 2007

The American Journal of Pathology

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To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful , as preventive and curative means , for the treatment of patients with liver damage. The liver has a remarkable ability to respond to injuries inflicted by various causes, such as partial hepatectomy, toxic exposure, and virus infection.1,2 Hepatocytes, which are liver parenchymal cells and normally in the quiescent G 0 phase, re-enter the cell cycle after injury to restore its mass, architecture, and function. In this process, a number of growth factors and cytokines have been reported to be involved. [3][4][5][6][7][8][9] For example, hepatocyte growth factor (HGF) functions as a potent mitogen for hepatocytes, 10 and the administration of HGF has been shown to ameliorate hepatic injury in animal models of fulminant hepatic failure. [11][12][13] It has also been shown that the introduction of hgf gene into rat cirrhotic livers using liposome with the hemagglutinating virus of Japan (HVJ) inhibits fibrogenesis and hepatocyte apoptosis, leading to the complete resolution of fibrosis and improvement of survival rate.14 Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family that includes IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, cardiotrophin-1, and novel neutrophin-1/B-cell-stimulating factor-3. [15][16][17][18] Mouse OSM receptor is composed of the gp130 subunit, common to all of the IL-6 family cytokines, and an OSM-specific subunit (hereafter called OSM-specific receptor; OSM-R).19 Binding of OSM to its receptor complex activates Janus tyrosine kinases (Jak1, Jak2, and Tyk2), which in turn activates downstream signaling pathways, including SHP-2 tyrosine phosphatase and signal transducer and activator of transcription protein 3 (STAT3). Recently, OSM has been shown to induce maturation of mou...

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Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice

Cited by 140 publications

References 51 publications

Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration

Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration

Interleukin-31 and Oncostatin-M Mediate Distinct Signaling Reactions and Response Patterns in Lung Epithelial Cells

Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

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