Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis

Anna P Lam, Jose D. Herazo-Maya, Joseph A. Sennello, Annette S. Flozak, Susan Renee Russell, Gokhan M. Mutlu, GR Scott Budinger, Ramanu DasGupta, John Varga, Naftal Kaminski, Cara Gottardi*

*Corresponding author for this work

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Rationale: Wnt/b-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. Objectives: To determine whether theWnt coreceptor Lrp5 drives pulmonaryfibrosis in mice and is predictive of disease severity in humans. Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-b.We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF). Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of b-catenin signaling by the small molecular inhibitor of b-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-b, Lrp5 null mice were not protected against lung fibrosis induced by TGF-b. Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-b signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.

Original languageEnglish (US)
Pages (from-to)185-195
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume190
Issue number2
DOIs
StatePublished - Jul 15 2014

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Idiopathic Pulmonary Fibrosis
Transforming Growth Factors
Fibrosis
Catenins
Lung
Disease Progression
Wnt Signaling Pathway
Bleomycin
Blood Cells
Alveolar Epithelial Cells
Null Lymphocytes
Pulmonary Fibrosis
Adenoviridae
Bone Marrow Cells
Patient Selection
Leukocytes
Transplantation
Gene Expression

Keywords

  • Lung fibrosis
  • Peripheral blood mononuclear cell
  • Wnt/b-catenin signalling

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Lam, Anna P ; Herazo-Maya, Jose D. ; Sennello, Joseph A. ; Flozak, Annette S. ; Russell, Susan Renee ; Mutlu, Gokhan M. ; Budinger, GR Scott ; DasGupta, Ramanu ; Varga, John ; Kaminski, Naftal ; Gottardi, Cara. / Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. In: American journal of respiratory and critical care medicine. 2014 ; Vol. 190, No. 2. pp. 185-195.
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title = "Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis",
abstract = "Rationale: Wnt/b-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. Objectives: To determine whether theWnt coreceptor Lrp5 drives pulmonaryfibrosis in mice and is predictive of disease severity in humans. Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-b.We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF). Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of b-catenin signaling by the small molecular inhibitor of b-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-b, Lrp5 null mice were not protected against lung fibrosis induced by TGF-b. Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-b signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.",
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Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. / Lam, Anna P; Herazo-Maya, Jose D.; Sennello, Joseph A.; Flozak, Annette S.; Russell, Susan Renee; Mutlu, Gokhan M.; Budinger, GR Scott; DasGupta, Ramanu; Varga, John; Kaminski, Naftal; Gottardi, Cara.

In: American journal of respiratory and critical care medicine, Vol. 190, No. 2, 15.07.2014, p. 185-195.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis

AU - Lam, Anna P

AU - Herazo-Maya, Jose D.

AU - Sennello, Joseph A.

AU - Flozak, Annette S.

AU - Russell, Susan Renee

AU - Mutlu, Gokhan M.

AU - Budinger, GR Scott

AU - DasGupta, Ramanu

AU - Varga, John

AU - Kaminski, Naftal

AU - Gottardi, Cara

PY - 2014/7/15

Y1 - 2014/7/15

N2 - Rationale: Wnt/b-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. Objectives: To determine whether theWnt coreceptor Lrp5 drives pulmonaryfibrosis in mice and is predictive of disease severity in humans. Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-b.We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF). Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of b-catenin signaling by the small molecular inhibitor of b-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-b, Lrp5 null mice were not protected against lung fibrosis induced by TGF-b. Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-b signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.

AB - Rationale: Wnt/b-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. Objectives: To determine whether theWnt coreceptor Lrp5 drives pulmonaryfibrosis in mice and is predictive of disease severity in humans. Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-b.We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF). Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of b-catenin signaling by the small molecular inhibitor of b-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-b production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-b, Lrp5 null mice were not protected against lung fibrosis induced by TGF-b. Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-b signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.

KW - Lung fibrosis

KW - Peripheral blood mononuclear cell

KW - Wnt/b-catenin signalling

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