Gremlin-mediated Decrease in Bone Morphogenetic Protein Signaling Promotes Pulmonary Fibrosis
| Autor: | Katri Koli, Tim D. Oury, Corrine R. Kliment, Pamela Lindholm, Kaisa Salmenkivi, Jorma Keski-Oja, Merja Johanna Ryynänen, Marjukka Myllärniemi, Vuokko L. Kinnula |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Pulmonary and Respiratory Medicine
medicine.medical_specialty Bone Morphogenetic Protein 7 Pulmonary Fibrosis G. Interstitial Lung Disease Down-Regulation Critical Care and Intensive Care Medicine Bone morphogenetic protein Transforming Growth Factor beta1 03 medical and health sciences Mice 0302 clinical medicine Fibrosis Transforming Growth Factor beta Internal medicine Cell Line Tumor Pulmonary fibrosis medicine Animals Humans Tissue homeostasis 030304 developmental biology 0303 health sciences biology business.industry Asbestos Transforming growth factor beta respiratory system medicine.disease respiratory tract diseases 3. Good health BMPR2 Up-Regulation Bone morphogenetic protein 7 Disease Models Animal Endocrinology 030220 oncology & carcinogenesis Bone Morphogenetic Proteins biology.protein Cancer research Intercellular Signaling Peptides and Proteins business Gremlin (protein) Signal Transduction |
| Popis: | Members of the transforming growth factor (TGF)-beta superfamily, including TGF-betas and bone morphogenetic proteins (BMPs), are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the BMP antagonist, gremlin, is highly up-regulated in idiopathic pulmonary fibrosis (IPF).To investigate the role of gremlin in the regulation of BMP signaling in pulmonary fibrosis.Progressive asbestos-induced fibrosis in the mouse was used as a model of human IPF. TGF-beta and BMP expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of gremlin induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of gremlin inhibition was tested by administration of BMP-7 to mice after asbestos exposure.Gremlin mRNA levels were up-regulated in the asbestos-exposed mouse lungs, which is in agreement with the human IPF biopsy data. Down-regulation of BMP signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced gremlin expression could be prevented by inhibitors of the TGF-beta receptor and also by inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase pathways. BMP-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice.The TGF-beta and BMP signaling balance is important for lung regenerative events and is significantly perturbed in pulmonary fibrosis. Rescue of BMP signaling activity may represent a potential beneficial strategy for treating human pulmonary fibrosis. |
| Databáze: | OpenAIRE |
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