Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis.
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung.


RESULTS
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.


CONCLUSIONS
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.
Pardo
Annie
A
Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Gibson
Kevin
K
Cisneros
José
J
Richards
Thomas J
TJ
Yang
Yinke
Y
Becerril
Carina
C
Yousem
Samueal
S
Herrera
Iliana
I
Ruiz
Victor
V
Selman
Moisés
M
Kaminski
Naftali
N
D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D053495:Osteopontin; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000378:metabolism* / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D011994:Recombinant Proteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D020781:Matrix Metalloproteinase 1