Up-Regulation and Profibrotic Role of Osteopontin in Human Idiopathic Pulmonary Fibrosis

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung.Methods and FindingsUsing 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 αvβ3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti-αvβ3. 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.ConclusionsOur 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.

Anti-Inflammatory Effects of αv Integrin Antagonism in Acute Kidney Allograft Rejection

“…55,56 Recently, it has also been shown that osteopontin-mediated alveolar epithelial cell migration and fibroblast migration and proliferation could be inhibited by an antibody to ␣ v ␤ 3 integrin. 57 These data confirm the results with a decrease in tubular epithelia-induced migration of macrophages and fibroblasts by S247.…”

Essential Role of Osteopontin in Smoking-Related Interstitial Lung Diseases

“…Alveolar epithelial cells type II were positive for OPN in both diseases. Pardo et al 22 have previously shown that in IPF, mainly alveolar epithelial cells type II produce OPN. However, our findings clearly indicate that in PLCH and DIP macrophages also contribute to the increase in OPN production.…”

Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells for Inhibiting Myofibroblastic Differentiation of Irradiated Human Lung Fibroblasts

“…WISP-1 is a Wnt target gene that is overexpressed in lung fibrosis (Pardo et al 2005;Königshoff et al 2009). Furthermore, inhibition of WISP-1 attenuates the progression of fibrosis in vivo (Königshoff et al 2009).…”

“…Certain components of the canonical Wnt/β-catenin signaling pathway have been reported to play a role in lung fibrosis, including Wnt-inducible signaling protein-1 (WISP-1) and frequently rearranged in advanced T cell lymphomas-1 (FRAT1, an inhibitor of GSK-3β-mediated phosphorylation of β-catenin) (Pardo et al 2005;Königshoff et al 2009). In addition, Gurung et al (2009) have shown that irradiation of human lung fibroblasts (HLFs) results in activation of Wnt/β-catenin signaling.…”