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Gremlin-mediated Decrease in Bone Morphogenetic Protein Signaling Promotes Pulmonary Fibrosis

¹ Division of Pulmonary Medicine, Department of Medicine, and ² Departments of Virology and Pathology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; and ³ Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Katri Koli, Ph.D., University of Helsinki, Biomedicum/A506, P.O. Box 63, Haartmaninkatu 8, 00014 Helsinki, Finland. E-mail: katri.koli{at}helsinki.fi

Rationale: Members of the transforming growth factor (TGF)-β superfamily, including TGF-βs 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).

Objectives: 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-β 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: 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-β 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-β 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-β

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Gremlin is up-regulated in the lungs of patients with idiopathic pulmonary fibrosis. The role of gremlin in the regulation of bone morphogenetic protein (BMP) signaling in association with lung fibrosis had not been studied previously. What This Study Adds to the Field Gremlin induces lung fibrosis in the mouse and human lung via decreased BMP-signaling and increased transforming growth factor-β signaling. This effect can be inhibited by BMP-7 administration to the mouse.