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 language | English (US) |
|---|---|
| Pages (from-to) | 185-195 |
| Number of pages | 11 |
| Journal | American journal of respiratory and critical care medicine |
| Volume | 190 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 15 2014 |
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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
}
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 journal › Article
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
UR - http://www.scopus.com/inward/record.url?scp=84906926881&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906926881&partnerID=8YFLogxK
U2 - 10.1164/rccm.201401-0079OC
DO - 10.1164/rccm.201401-0079OC
M3 - Article
C2 - 24921217
AN - SCOPUS:84906926881
VL - 190
SP - 185
EP - 195
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 2
ER -