Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis

Abstract

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.

Klotho antagonizes pulmonary fibrosis through suppressing pulmonary fibroblasts activation, migration, and extracellular matrix production: a therapeutic implication for idiopathic pulmonary fibrosis

“…Our observation that mouse rKL along was sufficient to antagonize fibrosis in pulmonary fibroblasts is inconsistent with a recent finding that FGF23 is required for human rKL to take anti-fibrotic effect [13].…”

“…Previously, AGING the declines of KL in serum from IPF patients [13] as well as in several mouse pulmonary fibrosis models [13,15,16] imply the involvement of KL in the pathogenesis of pulmonary fibrosis. Further clues of the anti-fibrotic potential of KL in the lung include Klheterozygous hypomorphic allele mice displayed exacerbated asbestos- [16] and bleomycin- [13] induced pulmonary fibrosis, and that both recombinant KL (rKL) supplementation and Kl-overexpression attenuated pulmonary fibrosis response. Despite multiple efforts have been made to evaluate the effect of KL on the reverse of hallmarks of aging lung [8], such as cellular senescence [17], mitochondrial dysfunction [16], and stem cells exhaustion [18], the molecular mechanism underlying the protective effect of KL against pulmonary fibrosis remains murky, especially KL's regulatory role in pulmonary fibroblasts, the effector cells during the development of IPF [19].…”

“…KL has long been characterized as an anti-aging molecule with both membrane bound and soluble forms [10], whose deficiency renders multiple organs, such as kidney [11], heart [12], and lung [13], more susceptible to fibrosis, a common feature of aging [14]. Previously, AGING the declines of KL in serum from IPF patients [13] as well as in several mouse pulmonary fibrosis models [13,15,16] imply the involvement of KL in the pathogenesis of pulmonary fibrosis. Further clues of the anti-fibrotic potential of KL in the lung include Klheterozygous hypomorphic allele mice displayed exacerbated asbestos- [16] and bleomycin- [13] induced pulmonary fibrosis, and that both recombinant KL (rKL) supplementation and Kl-overexpression attenuated pulmonary fibrosis response.…”

Targeting Aging Pathways in Chronic Obstructive Pulmonary Disease

“…FGF23 is secreted by osteocytes and is important for regulating phosphate [ 131 ]. The FGF23/klotho signaling pathway has been studied in several inflammatory diseases such as heart disease, chronic kidney disease (CKD), and inflammatory airway diseases including COPD [ 132 , 133 , 134 , 135 , 136 ]. FGF23 levels have also been shown to be higher in COPD patients with more frequent exacerbations [ 137 ].…”

Fibroblast Growth Factor Receptor 4 Deficiency Mediates Airway Inflammation in the Adult Healthy Lung?

“…Total RNA was extracted from MTECs and murine lungs, as previously described (16). Real-time quantitative PCRs were performed using the following TaqMan probes: Fgfr4 Mm00433314, Fgf23 Mm00445621, Il-6 Mm00446190, Il-1beta Mm00434228, Tgf-beta1 Mm01178820, and Gapdh Mm99999915 (Invitrogen, Carlsbad, CA, USA).…”