Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung.Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lun...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2005-09-01
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| Series: | PLoS Medicine |
| Online Access: | http://europepmc.org/articles/PMC1198037?pdf=render |
| _version_ | 1819082877445341184 |
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| author | Annie Pardo Kevin Gibson José Cisneros Thomas J Richards Yinke Yang Carina Becerril Samueal Yousem Iliana Herrera Victor Ruiz Moisés Selman Naftali Kaminski |
| author_facet | Annie Pardo Kevin Gibson José Cisneros Thomas J Richards Yinke Yang Carina Becerril Samueal Yousem Iliana Herrera Victor Ruiz Moisés Selman Naftali Kaminski |
| author_sort | Annie Pardo |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung.Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients. To study the fibrosis-relevant effects of osteopontin we stimulated primary human lung fibroblasts and alveolar epithelial cells (A549) with recombinant osteopontin. Osteopontin induced a significant increase of migration and proliferation in both fibroblasts and epithelial cells. Epithelial growth was inhibited by the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) and antibody to CD44, while fibroproliferation was inhibited by GRGDS and antibody to alphavbeta3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti-alphavbeta3. In fibroblasts, osteopontin up-regulated tissue inhibitor of metalloprotease-1 and type I collagen, and down-regulated matrix metalloprotease-1 (MMP-1) expression, while in A549 cells it caused up-regulation of MMP-7. In human IPF lungs, osteopontin colocalized with MMP-7 in alveolar epithelial cells, and application of weakest link statistical models to microarray data suggested a significant interaction between osteopontin and MMP-7.Our results provide a potential mechanism by which osteopontin secreted from the alveolar epithelium may exert a profibrotic effect in IPF lungs and highlight osteopontin as a potential target for therapeutic intervention in this incurable disease. |
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| format | Article |
| id | doaj.art-f9ac401bdea44c3a8a183bc7312ed8c8 |
| institution | Directory Open Access Journal |
| issn | 1549-1277 1549-1676 |
| language | English |
| last_indexed | 2024-12-21T20:23:39Z |
| publishDate | 2005-09-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Medicine |
| spelling | doaj.art-f9ac401bdea44c3a8a183bc7312ed8c82022-12-21T18:51:26ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762005-09-0129e25110.1371/journal.pmed.0020251Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis.Annie PardoKevin GibsonJosé CisnerosThomas J RichardsYinke YangCarina BecerrilSamueal YousemIliana HerreraVictor RuizMoisés SelmanNaftali KaminskiIdiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung.Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients. To study the fibrosis-relevant effects of osteopontin we stimulated primary human lung fibroblasts and alveolar epithelial cells (A549) with recombinant osteopontin. Osteopontin induced a significant increase of migration and proliferation in both fibroblasts and epithelial cells. Epithelial growth was inhibited by the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) and antibody to CD44, while fibroproliferation was inhibited by GRGDS and antibody to alphavbeta3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti-alphavbeta3. In fibroblasts, osteopontin up-regulated tissue inhibitor of metalloprotease-1 and type I collagen, and down-regulated matrix metalloprotease-1 (MMP-1) expression, while in A549 cells it caused up-regulation of MMP-7. In human IPF lungs, osteopontin colocalized with MMP-7 in alveolar epithelial cells, and application of weakest link statistical models to microarray data suggested a significant interaction between osteopontin and MMP-7.Our results provide a potential mechanism by which osteopontin secreted from the alveolar epithelium may exert a profibrotic effect in IPF lungs and highlight osteopontin as a potential target for therapeutic intervention in this incurable disease.http://europepmc.org/articles/PMC1198037?pdf=render |
| spellingShingle | Annie Pardo Kevin Gibson José Cisneros Thomas J Richards Yinke Yang Carina Becerril Samueal Yousem Iliana Herrera Victor Ruiz Moisés Selman Naftali Kaminski Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Medicine |
| title | Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. |
| title_full | Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. |
| title_fullStr | Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. |
| title_full_unstemmed | Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. |
| title_short | Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. |
| title_sort | up regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis |
| url | http://europepmc.org/articles/PMC1198037?pdf=render |
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