Submitted on June 27, 2007
Accepted on November 1, 2007
Gremlin-Mediated Decrease in Bone Morphogenetic Protein Signaling Promotes Pulmonary Fibrosis
Marjukka Myllarniemi1, Pamela Lindholm1, Merja J Ryynanen2, Corrine R Kliment3, Kaisa Salmenkivi2, Jorma Keski-Oja2, Vuokko L Kinnula1, Tim D Oury3, and Katri Koli2*
1 Department of Medicine, Division of Pulmonary Medicine, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland,
2 Department of Virology and Pathology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland,
3 Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, USA
* To whom correspondence should be addressed. E-mail: katri.koli{at}helsinki.fi.
Rationale Members of the transforming growth factor (TGF)-
superfamily, including TGF-s 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.
Objectives The study was undertaken 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 idiopathic pulmonary fibrosis. TGF- 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.
Measurements and Main Results In the asbestos-exposed mouse lungs gremlin mRNA levels were up-regulated, which is in agreement with the human idiopathic pulmonary fibrosis 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- receptor and also by inhibitors of the MEK/ERK pathways. BMP-7 treatment reduced significantly hydroxyproline contents in the asbestos-treated mice.
Conclusions The TGF- 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.
Key words: gremlin, pulmonary fibrosis, bone morphogenetic protein, transforming growth factor-beta
