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

Our plain-English summary of Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis, by M. Myllärniemi, P. Lindholm, M.J. Ryynänen, et al (American Journal of Respiratory and Critical Care Medicine, 2008).

The study

• Authors: M. Myllärniemi, P. Lindholm, M.J. Ryynänen, C.R. Kliment, K. Salmenkivi, J. Keski-Oja, V.L. Kinnula, T.D. Oury, K. Koli
• Journal: American Journal of Respiratory and Critical Care Medicine
• Published: 2008;177(3):321-9
• Cited by: 154 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Rationale: 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).

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-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.

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-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.

In plain English

This laboratory study looked at whether gremlin, a protein that blocks signaling by bone morphogenetic proteins (BMPs), plays a part in lung scarring (fibrosis). The authors placed a single 0.1-mg dose of crocidolite asbestos into the lungs of C57BL/6 mice, or titanium dioxide as an inert control, with five mice per group. They also examined lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) and from one patient with asbestosis, and they ran experiments on cultured human lung cells. At 14 days, gremlin rose in asbestos-exposed mouse lungs while markers of BMP signaling fell. Intense gremlin staining was also seen in IPF biopsies and in the asbestosis specimen. In cultured bronchial cells, asbestos raised gremlin about fourfold at one concentration and reduced BMP signaling activity by nearly 60%. Drugs blocking the TGF-beta receptor or the MEK enzyme prevented the gremlin rise. In asbestos-exposed mice, BMP-7 injections from Day 7 to Day 14 reduced the asbestos-induced rise in lung hydroxyproline, a collagen marker, by about 50%. The authors concluded that the balance between TGF-beta and BMP signaling regulates fibrosis development, and that treatments might aim to enhance BMP signaling.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining an animal experiment (mouse model of asbestos-induced lung fibrosis used as a model of human IPF), cell culture experiments, and analysis of human lung biopsies
• Who was studied: C57BL/6 mice (five per group, killed at Day 3 or Day 14); cultured normal human bronchial epithelial (NHBE) cells and A549 lung adenocarcinoma cells; human lung biopsies from patients with biopsy-proven IPF/UIP or asbestosis and from control lung tissue, collected under approval of the Helsinki University Central Hospital ethics committee, Finland
• Exposure: A single intratracheal dose of 0.1 mg crocidolite asbestos in mice, compared with titanium dioxide as an inert control; cultured cells were also exposed to asbestos in the laboratory; some asbestos-exposed mice received BMP-7 injections from Day 7 to Day 14
• Main results:
  • In asbestos-exposed mice, gremlin mRNA levels were clearly increased at 14 days. Noggin and chordin mRNA levels were unaltered.
  • In asbestos-exposed mouse lungs, expression of the BMP target gene Id1 was significantly reduced, and staining for phosphorylated Smad1/5/8 (a sign of BMP signaling) was almost undetectable.
  • In human lungs, intense gremlin staining was found in the interstitium of IPF biopsies and in a specimen from one patient with asbestos-induced pulmonary fibrosis. Id1 mRNA was significantly reduced in IPF lungs.
  • In cultured normal human bronchial epithelial cells, asbestos at one concentration induced an approximately fourfold increase in gremlin mRNA, and BMP signaling activity was reduced by nearly 60% in asbestos-treated cells.
  • In these cells, asbestos increased TGF-beta signaling activity by more than 10-fold at 24 hours. The TGF-beta receptor inhibitor SB431542 completely prevented the asbestos-induced rise in gremlin mRNA.
  • Inhibitors of the MEK enzyme blocked the asbestos-induced rise in gremlin in cultured bronchial epithelial cells. They did not affect gremlin induction by TGF-beta1.
  • In asbestos-exposed mouse lungs, phosphorylated Smad2 (a TGF-beta signaling marker) was increased approximately 1.5-fold. TGF-beta mRNA levels were not significantly altered at 14 days.
  • In asbestos-exposed mice, BMP-7 treatment reduced the asbestos-induced increase in lung hydroxyproline (an indicator of collagen deposition) by approximately 50%.
  • In BMP-7-treated mice there was a tendency toward fewer inflammatory cells in lung lavage fluid, but this was not statistically significant.
• The authors' conclusion: The authors concluded that the balance between TGF-beta and BMP signaling is an important regulator of fibrotic disease development. In their view, new treatment strategies might aim at inhibiting TGF-beta and/or enhancing BMP signaling.
• Limitations the authors state:
  • The authors noted that studying the early changes of lung fibrosis in humans is challenging, so their suggestion that gremlin contributes to early fibrosis rests on mouse findings.

Topics

Medical terms in this study, explained in our Lexicon: Pulmonary Fibrosis, Idiopathic, Fibrosis, Asbestos Exposure, Biopsy.

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• Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats — T.D. Perdue, A.R. Brody (1994)

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