schliessen

Filtern

 

Bibliotheken

Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed.... Full description

Journal Title: Nature medicine 2013-12, Vol.19 (12), p.1617-1624
Main Author: Henderson, Neil C
Other Authors: Arnold, Thomas D , Katamura, Yoshio , Giacomini, Marilyn M , Rodriguez, Juan D , McCarty, Joseph H , Pellicoro, Antonella , Raschperger, Elisabeth , Betsholtz, Christer , Ruminski, Peter G , Griggs, David W , Prinsen, Michael J , Maher, Jacquelyn J , Iredale, John P , Lacy-Hulbert, Adam , Adams, Ralf H , Sheppard, Dean
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States
ID: ISSN: 1078-8956
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: cdi_proquest_miscellaneous_1465863529
title: Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
format: Article
creator:
  • Henderson, Neil C
  • Arnold, Thomas D
  • Katamura, Yoshio
  • Giacomini, Marilyn M
  • Rodriguez, Juan D
  • McCarty, Joseph H
  • Pellicoro, Antonella
  • Raschperger, Elisabeth
  • Betsholtz, Christer
  • Ruminski, Peter G
  • Griggs, David W
  • Prinsen, Michael J
  • Maher, Jacquelyn J
  • Iredale, John P
  • Lacy-Hulbert, Adam
  • Adams, Ralf H
  • Sheppard, Dean
subjects:
  • Animals
  • Annan klinisk medicin
  • Cell- och molekylärbiologi
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Female
  • Fibrosis - genetics
  • Gene Targeting
  • Integrin alphaV - genetics
  • Integrin alphaV - metabolism
  • Kidney - metabolism
  • Kidney - pathology
  • Kidney Diseases - genetics
  • Kidney Diseases - pathology
  • Klinisk medicin
  • Liver Cirrhosis - genetics
  • Liver Cirrhosis - pathology
  • Male
  • Medicin och hälsovetenskap
  • Medicinska och farmaceutiska grundvetenskaper
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myofibroblasts - metabolism
  • Myofibroblasts - pathology
  • Pulmonary Fibrosis - genetics
  • Pulmonary Fibrosis - pathology
  • Signal Transduction - physiology
ispartof: Nature medicine, 2013-12, Vol.19 (12), p.1617-1624
description: Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
  • 1546-170X
url: Link


@attributes
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
RANK2.810875
LOCALfalse
PrimoNMBib
record
control
sourceidproquest_swepu
recordidTN_cdi_proquest_miscellaneous_1465863529
sourceformatXML
sourcesystemPC
sourcerecordid1465863529
originalsourceidFETCH-LOGICAL-12939-24bb3a30b92144bbbf0ce30f59b3e9358a3b5ca1383d4b95781941b1360427860
addsrcrecordideNplkc1u1TAQhS0EoqUg3gB5B5sU_8SJvURVaZEqsWml7qxx7iQ1JPbFdlr1sXgRnglf7qULWIzmaPSdY1mHkLecnXIm9cewnEqhxTNyzFXbNbxnt8-rZr1utFHdEXmV8zfGmGTKvCRHohW865U8JtM1pAmLDxONI_318576UHBKPlC_wVD86DFToENMSJc447DOkOgWyt0DPNJyB4UmnOqxVG70LsXscw2hGe8xwUxjmiDk1-TFCHPGN4d9Qm4-n1-fXTZXXy--nH26argw0jSidU6CZM4I3lbtRjagZKMyTqKRSoN0agAutdy0zqhec9Nyx2XHWtHrjp0Qs8_ND7hdnd0mv0B6tBF81XFjD_fvfjc2o-XVZyQTpno_7L0V_LFiLnbxecB5hoBxzZa3ndKdVH_Q93t0qP_NCcenhzizu0ZsWOyukUq-O4SubsHNE_e3ggo0_0QNvkDxMZQEfv4v8DdkE5db
sourcetypeOpen Access Repository
isCDItrue
recordtypearticle
pqid1465863529
display
typearticle
titleTargeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
creatorHenderson, Neil C ; Arnold, Thomas D ; Katamura, Yoshio ; Giacomini, Marilyn M ; Rodriguez, Juan D ; McCarty, Joseph H ; Pellicoro, Antonella ; Raschperger, Elisabeth ; Betsholtz, Christer ; Ruminski, Peter G ; Griggs, David W ; Prinsen, Michael J ; Maher, Jacquelyn J ; Iredale, John P ; Lacy-Hulbert, Adam ; Adams, Ralf H ; Sheppard, Dean
creatorcontribHenderson, Neil C ; Arnold, Thomas D ; Katamura, Yoshio ; Giacomini, Marilyn M ; Rodriguez, Juan D ; McCarty, Joseph H ; Pellicoro, Antonella ; Raschperger, Elisabeth ; Betsholtz, Christer ; Ruminski, Peter G ; Griggs, David W ; Prinsen, Michael J ; Maher, Jacquelyn J ; Iredale, John P ; Lacy-Hulbert, Adam ; Adams, Ralf H ; Sheppard, Dean
descriptionMyofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
identifier
0ISSN: 1078-8956
1ISSN: 1546-170X
2EISSN: 1546-170X
3DOI: 10.1038/nm.3282
4PMID: 24216753
languageeng
publisherUnited States
subjectAnimals ; Annan klinisk medicin ; Cell- och molekylärbiologi ; Cells, Cultured ; Drug Evaluation, Preclinical ; Female ; Fibrosis - genetics ; Gene Targeting ; Integrin alphaV - genetics ; Integrin alphaV - metabolism ; Kidney - metabolism ; Kidney - pathology ; Kidney Diseases - genetics ; Kidney Diseases - pathology ; Klinisk medicin ; Liver Cirrhosis - genetics ; Liver Cirrhosis - pathology ; Male ; Medicin och hälsovetenskap ; Medicinska och farmaceutiska grundvetenskaper ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myofibroblasts - metabolism ; Myofibroblasts - pathology ; Pulmonary Fibrosis - genetics ; Pulmonary Fibrosis - pathology ; Signal Transduction - physiology
ispartofNature medicine, 2013-12, Vol.19 (12), p.1617-1624
lds50peer_reviewed
oafree_for_read
citedbyFETCH-LOGICAL-12939-24bb3a30b92144bbbf0ce30f59b3e9358a3b5ca1383d4b95781941b1360427860
citesFETCH-LOGICAL-12939-24bb3a30b92144bbbf0ce30f59b3e9358a3b5ca1383d4b95781941b1360427860
links
openurl$$Topenurl_article
thumbnail$$Usyndetics_thumb_exl
backlink
0$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24216753$$D View this record in MEDLINE/PubMed
1$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:127893029$$DView record from Swedish Publication Index
search
creatorcontrib
0Henderson, Neil C
1Arnold, Thomas D
2Katamura, Yoshio
3Giacomini, Marilyn M
4Rodriguez, Juan D
5McCarty, Joseph H
6Pellicoro, Antonella
7Raschperger, Elisabeth
8Betsholtz, Christer
9Ruminski, Peter G
10Griggs, David W
11Prinsen, Michael J
12Maher, Jacquelyn J
13Iredale, John P
14Lacy-Hulbert, Adam
15Adams, Ralf H
16Sheppard, Dean
title
0Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
1Nature medicine
addtitleNat Med
descriptionMyofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
subject
0Animals
1Annan klinisk medicin
2Cell- och molekylärbiologi
3Cells, Cultured
4Drug Evaluation, Preclinical
5Female
6Fibrosis - genetics
7Gene Targeting
8Integrin alphaV - genetics
9Integrin alphaV - metabolism
10Kidney - metabolism
11Kidney - pathology
12Kidney Diseases - genetics
13Kidney Diseases - pathology
14Klinisk medicin
15Liver Cirrhosis - genetics
16Liver Cirrhosis - pathology
17Male
18Medicin och hälsovetenskap
19Medicinska och farmaceutiska grundvetenskaper
20Mice
21Mice, Inbred C57BL
22Mice, Transgenic
23Myofibroblasts - metabolism
24Myofibroblasts - pathology
25Pulmonary Fibrosis - genetics
26Pulmonary Fibrosis - pathology
27Signal Transduction - physiology
issn
01078-8956
11546-170X
21546-170X
fulltextfalse
rsrctypearticle
creationdate2013
recordtypearticle
recordideNplkc1u1TAQhS0EoqUg3gB5B5sU_8SJvURVaZEqsWml7qxx7iQ1JPbFdlr1sXgRnglf7qULWIzmaPSdY1mHkLecnXIm9cewnEqhxTNyzFXbNbxnt8-rZr1utFHdEXmV8zfGmGTKvCRHohW865U8JtM1pAmLDxONI_318576UHBKPlC_wVD86DFToENMSJc447DOkOgWyt0DPNJyB4UmnOqxVG70LsXscw2hGe8xwUxjmiDk1-TFCHPGN4d9Qm4-n1-fXTZXXy--nH26argw0jSidU6CZM4I3lbtRjagZKMyTqKRSoN0agAutdy0zqhec9Nyx2XHWtHrjp0Qs8_ND7hdnd0mv0B6tBF81XFjD_fvfjc2o-XVZyQTpno_7L0V_LFiLnbxecB5hoBxzZa3ndKdVH_Q93t0qP_NCcenhzizu0ZsWOyukUq-O4SubsHNE_e3ggo0_0QNvkDxMZQEfv4v8DdkE5db
startdate201312
enddate201312
creator
0Henderson, Neil C
1Arnold, Thomas D
2Katamura, Yoshio
3Giacomini, Marilyn M
4Rodriguez, Juan D
5McCarty, Joseph H
6Pellicoro, Antonella
7Raschperger, Elisabeth
8Betsholtz, Christer
9Ruminski, Peter G
10Griggs, David W
11Prinsen, Michael J
12Maher, Jacquelyn J
13Iredale, John P
14Lacy-Hulbert, Adam
15Adams, Ralf H
16Sheppard, Dean
scope
0CGR
1CUY
2CVF
3ECM
4EIF
5NPM
6AAYXX
7CITATION
87X8
9ADTPV
10AOWAS
11D8T
sort
creationdate201312
titleTargeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
authorHenderson, Neil C ; Arnold, Thomas D ; Katamura, Yoshio ; Giacomini, Marilyn M ; Rodriguez, Juan D ; McCarty, Joseph H ; Pellicoro, Antonella ; Raschperger, Elisabeth ; Betsholtz, Christer ; Ruminski, Peter G ; Griggs, David W ; Prinsen, Michael J ; Maher, Jacquelyn J ; Iredale, John P ; Lacy-Hulbert, Adam ; Adams, Ralf H ; Sheppard, Dean
facets
frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-12939-24bb3a30b92144bbbf0ce30f59b3e9358a3b5ca1383d4b95781941b1360427860
rsrctypearticles
prefilterarticles
languageeng
creationdate2013
topic
0Animals
1Annan klinisk medicin
2Cell- och molekylärbiologi
3Cells, Cultured
4Drug Evaluation, Preclinical
5Female
6Fibrosis - genetics
7Gene Targeting
8Integrin alphaV - genetics
9Integrin alphaV - metabolism
10Kidney - metabolism
11Kidney - pathology
12Kidney Diseases - genetics
13Kidney Diseases - pathology
14Klinisk medicin
15Liver Cirrhosis - genetics
16Liver Cirrhosis - pathology
17Male
18Medicin och hälsovetenskap
19Medicinska och farmaceutiska grundvetenskaper
20Mice
21Mice, Inbred C57BL
22Mice, Transgenic
23Myofibroblasts - metabolism
24Myofibroblasts - pathology
25Pulmonary Fibrosis - genetics
26Pulmonary Fibrosis - pathology
27Signal Transduction - physiology
toplevelpeer_reviewed
creatorcontrib
0Henderson, Neil C
1Arnold, Thomas D
2Katamura, Yoshio
3Giacomini, Marilyn M
4Rodriguez, Juan D
5McCarty, Joseph H
6Pellicoro, Antonella
7Raschperger, Elisabeth
8Betsholtz, Christer
9Ruminski, Peter G
10Griggs, David W
11Prinsen, Michael J
12Maher, Jacquelyn J
13Iredale, John P
14Lacy-Hulbert, Adam
15Adams, Ralf H
16Sheppard, Dean
collection
0Medline
1MEDLINE
2MEDLINE (Ovid)
3MEDLINE
4MEDLINE
5PubMed
6CrossRef
7MEDLINE - Academic
8SwePub
9SwePub Articles
10SWEPUB Freely available online
jtitleNature medicine
delivery
delcategoryRemote Search Resource
fulltextno_fulltext
addata
au
0Henderson, Neil C
1Arnold, Thomas D
2Katamura, Yoshio
3Giacomini, Marilyn M
4Rodriguez, Juan D
5McCarty, Joseph H
6Pellicoro, Antonella
7Raschperger, Elisabeth
8Betsholtz, Christer
9Ruminski, Peter G
10Griggs, David W
11Prinsen, Michael J
12Maher, Jacquelyn J
13Iredale, John P
14Lacy-Hulbert, Adam
15Adams, Ralf H
16Sheppard, Dean
formatjournal
genrearticle
ristypeJOUR
atitleTargeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
jtitleNature medicine
addtitleNat Med
date2013-12
risdate2013
volume19
issue12
spage1617
epage1624
pages1617-1624
issn
01078-8956
11546-170X
eissn1546-170X
abstractMyofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
copUnited States
pmid24216753
doi10.1038/nm.3282
oafree_for_read