Osteopontin, an Oxidant Stress Sensitive Cytokine, Up-regulates Collagen-I via Integrin αVβ3 Engagement and PI3K/pAkt/NFκB Signaling

Urtasun, Raquel; Lopategi, Aritz; George, Joseph; Leung, Tung Ming; Lu, Yongke; Wang, Xiaodong; Ge, Xiaodong; Fiel, M. Isabel; Nieto, Natalia

doi:10.1002/hep.24701

Cited by 216 publications

(200 citation statements)

References 35 publications

Supporting

Mentioning

177

Contrasting

Order By: Relevance

“…16 OPN is a matricellular cytokine highly involved in tissue remodeling. Previous work from our group showed that OPN is increased in drug-induced liver injury and fibrosis 17 and that Opn À / À mice were protected from hepatic fibrosis compared with WT mice. As we demonstrated that OPN has direct effects on fibrillar collagen-I, 17 we hypothesized that OPN could also delay fibrosis resolution, perhaps independently of the aforementioned mechanisms.…”

mentioning

confidence: 79%

“…Previous work from our group showed that OPN is increased in drug-induced liver injury and fibrosis 17 and that Opn À / À mice were protected from hepatic fibrosis compared with WT mice. As we demonstrated that OPN has direct effects on fibrillar collagen-I, 17 we hypothesized that OPN could also delay fibrosis resolution, perhaps independently of the aforementioned mechanisms. Thus, the aim of the present study was to compare the rate of fibrosis resolution after chronic TAA treatment in WT mice and in Opn À / À mice with particular emphasis on fibrillar collagen-I expression, the key protein involved in liver fibrosis.…”

mentioning

confidence: 79%

“…We proposed and demonstrated that OPN drives the fibrogenic response, among others, by directly regulating collagen-I deposition. 17 Therefore, because of the direct effects of OPN on regulating collagen-I protein expression, in this study, we hypothesized that OPN could also delay fibrosis resolution. To demonstrate this, we compared the rate of fibrosis resolution, with particular attention to fibrillar collagen-I, following chronic TAA treatment in WT mice and in Opn À / À mice.…”

Section: Opn and Fibrosis Resolutionmentioning

confidence: 95%

“…17 Moreover, the cell-and matrix-binding ability of OPN also appears to facilitate proper stromal and fibrillar collagen network organization. We proposed and demonstrated that OPN drives the fibrogenic response, among others, by directly regulating collagen-I deposition.…”

Section: Opn and Fibrosis Resolutionmentioning

confidence: 99%

See 3 more Smart Citations

Osteopontin delays resolution of liver fibrosis

Leung

Wang

Kitamura

et al. 2013

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

To date, considerable progress has been made both in the mechanisms driving liver fibrosis and in the prevention of disease progression. Resolution of liver fibrosis is an emerging field in hepatology; yet, the mediators involved remain elusive. Earlier work from our laboratory demonstrated that the matricellular cytokine osteopontin (OPN) is pro-fibrogenic by promoting hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition in vitro and in vivo and specifically by governing fibrillar collagen-I expression, the key pro-fibrogenic protein. Here we hypothesized that OPN could also delay the resolution of liver fibrosis by sustaining collagen-I synthesis or by preventing its degradation. To demonstrate this, wild-type (WT) and OPN-knockout (Opn À / À ) mice were administered thioacetamide (TAA) in the drinking water for 4 months. Half of the mice were killed at 4 months to assess the extent of fibrosis at the peak of injury, and the rest of the mice were killed 2 months after TAA withdrawal to determine the rate of fibrosis resolution. Following TAA cessation, livers from Opn À / À mice showed no centrilobular and parenchymal necrosis along with faster ECM remodeling than WT mice. The latter was quantified by less fibrillar collagen-I immunostaining. Western blot analysis demonstrated a significant decrease in fibrillar collagen-I and in tissue inhibitor of metalloproteinase-1 (TIMP-1) in Opn À / À mice undergoing fibrosis resolution compared with WT mice. In conclusion, these results suggest that OPN delays liver fibrosis resolution due to sustained fibrillar collagen-I deposition; hence, inhibiting OPN could be an effective therapeutic strategy for resolving liver fibrosis.

show abstract

mentioning

confidence: 79%

mentioning

confidence: 79%

Section: Opn and Fibrosis Resolutionmentioning

confidence: 95%

Section: Opn and Fibrosis Resolutionmentioning

confidence: 99%

See 2 more Smart Citations

Osteopontin delays resolution of liver fibrosis

Leung

Wang

Kitamura

et al. 2013

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…The receptor for this protein is a m b 3 integrin, which is expressed by HSCs [47]. Conflicting results exist, however, with regard to the role of this chemokine in the development of liver fibrosis.…”

Section: Mediators That Stimulate Hsc Chemotaxismentioning

confidence: 99%

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

Copple

2014

Curr Pathobiol Rep

View full text Add to dashboard Cite

Hepatic stellate cells (HSCs) are the main extracellular matrix-producing cell type in the liver. These cells exist in a quiescent state in normal liver and an activated state in damaged liver. During quiescence, HSCs store and release various retinoids. After injury to the liver, however, various protein and non-protein mediators are released from cells that stimulate HSCs to differentiate into myofibroblasts, a process termed activation. Activated HSCs begin to express a-smooth muscle actin and migrate to sites of injury through chemotaxis. Within the damaged region of liver, these cells become contractile and produce growth factors that promote hepatocyte replication and angiogenesis, produce extracellular matrix that forms the scaffold for liver repair, and produce proteins that modulate immune cell function. Once liver repair is complete and liver function is restored, HSCs revert back to a quiescent phenotype or die by apoptosis. If liver injury becomes chronic, however, these processes persist resulting in the formation of an extensive scar (i.e., fibrosis) that ultimately leads to liver failure. Because of the importance of these cells to the development of liver fibrosis, there has been extensive research into understanding the mechanisms that drive HSC activation after injury and the mechanisms that regulate reversion of these cells back to quiescence after resolution of injury. In addition, there has been great interest in identifying the various functions of HSCs after acute and chronic injury. The aim of this review is to briefly discuss the phenotypic changes that occur in HSCs after acute and chronic liver injury and to highlight some of the important functions of these cells during repair of the liver.

show abstract

Integrins and heparan sulfate proteoglycans on hepatic stellate cells (HSC) are novel receptors for HSC‐derived exosomes

Chen

Brigstock

2016

FEBS Letters

View full text Add to dashboard Cite

Exosomes mediate intercellular microRNA delivery between hepatic stellate cells (HSC), the principal fibrosis-producing cells in the liver. The purpose of this study was to identify receptors on HSC for HSC-derived exosomes, which bind to HSC rather than to hepatocytes. Our findings indicate that exosome binding to HSC is blocked by treating HSC with RGD, EDTA, integrin αv or β1 siRNAs, integrin αvβ3 or α5β1 neutralizing antibodies, heparin, or sodium chlorate. Furthermore, exosome cargo delivery and exosome-regulated functions in HSC, including expression of fibrosis- or activation-associated genes and/or miR-214 target gene regulation, are dependent on cellular integrin αvβ3, integrin α5β1, or heparan-sulfate proteolgycans (HSPG). Thus, integrins and HSPG mediate the binding of HSC-derived exosomes to HSC as well as the delivery and intracellular action of the exosomal payload.

show abstract

Osteopontin, an Oxidant Stress Sensitive Cytokine, Up-regulates Collagen-I via Integrin αVβ3 Engagement and PI3K/pAkt/NFκB Signaling

Cited by 216 publications

References 35 publications

Osteopontin delays resolution of liver fibrosis

Osteopontin delays resolution of liver fibrosis

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

Integrins and heparan sulfate proteoglycans on hepatic stellate cells (HSC) are novel receptors for HSC‐derived exosomes

Contact Info

Product

Resources

About