TY - JOUR
T1 - Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis
AU - Barnes, Jarrod W.
AU - Duncan, Dawn
AU - Helton, Scott
AU - Hutcheson, Samuel
AU - Kurundkar, Deepali
AU - Logsdon, Naomi J.
AU - Locy, Morgan
AU - Garth, Jaleesa
AU - Denson, Rebecca
AU - Farver, Carol
AU - Vo, Hai T.
AU - King, Gwendalyn
AU - Kentrup, Dominik
AU - Faul, Christian
AU - Kulkarni, Tejaswini
AU - De Andrade, Joao A.
AU - Yu, Zhihong
AU - Matalon, Sadis
AU - Thannickal, Victor J.
AU - Krick, Stefanie
N1 - Funding Information:
This work was supported by the Flight Attendant Medical Research Institute Grant YFAC152003 (to S. Krick), Cystic Fibrosis Foundation Grant CFF-KRICK1610 (to S. Krick), and National Institutes of Health Grants K99HL131866 and R00HL131866 (to J. W. Barnes) and R03AG059994 (to S. Krick).
Publisher Copyright:
© 2019, American Physiological Society. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an “age-suppressing” hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.
AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an “age-suppressing” hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.
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U2 - 10.1152/ajplung.00246.2018
DO - 10.1152/ajplung.00246.2018
M3 - Article
C2 - 31042083
AN - SCOPUS:85069266717
VL - 317
SP - L141-L154
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
SN - 1040-0605
IS - 1
ER -