Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis.
BACKGROUND
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).


OBJECTIVE
To investigate the role of gremlin in the regulation of BMP signaling in pulmonary fibrosis.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Myllärniemi
Marjukka
M
University of Helsinki, Biomedicum/A506, P.O. Box 63, Haartmaninkatu 8, 00014 Helsinki, Finland.
Lindholm
Pamela
P
Ryynänen
Merja J
MJ
Kliment
Corrine R
CR
Salmenkivi
Kaisa
K
Keski-Oja
Jorma
J
Kinnula
Vuokko L
VL
Oury
Tim D
TD
Koli
Katri
K
D000818:Animals; D001194:Asbestos / Q000009:adverse effects; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D015854:Up-Regulation; D016207:Cytokines
D001194:Asbestos; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C525819:BMP7 protein, human; C486399:GREM1 protein, human; C113178:Grem1 protein, mouse; D016207:Cytokines