Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrate that the levels of ACP5 are increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 are present in the sera of IPF patients with a diffusing capacity of the lungs for carbonmonoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protects mice from BLM-induced lung injury and fibrosis coupled with a significant reduction of fibroblast differentiation and proliferation. Mechanistic studies reveal that Acp5 is upregulated by transforming growth factor-β1 (TGF-β1) in a TGF-β receptor 1 (TGFβR1)/Smad family member 3 (Smad3)-dependent manner, after which Acp5 dephosphorylates p-β-catenin at serine 33 and threonine 41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promotes the differentiation, proliferation and migration of fibroblast. More importantly, the treatment of mice with Acp5 siRNA-loaded liposomes or Acp5 inhibitor reverses established lung fibrosis. In conclusions, Acp5 is involved in the initiation and progression of pulmonary fibrosis and strategies aimed at silencing or suppressing Acp5 could be considered as potential therapeutic approaches against pulmonary fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options
Under stimulation with fibrotic factors, such as transforming growth factor-β (TGF-β)[11], platelet-derived growth factor (PDGF)[12] and connective tissue growth factor (CTGF)[13], resident fibroblasts in the lung lesion transform into myofibroblasts, which are characterized by a spindle or stellate morphology with α-smooth muscle actin (α-SMA) stress fibers coupled with a hypersecretion phenotype due to which they produce copious amounts of fibrillary extracellular matrix (ECM) proteins, such as Collagen and Fibronectin
Expected, the expression of acid phosphatase 5 (ACP5) was efficiently silenced or enhanced following ACP5 siRNA or ACP5-plasmid transfection (Supplementary Fig. 1a, b). Both Western blot and RTPCR analyses demonstrated that fibroblast differentiation to myofibroblast was abrogated in ACP5 siRNA-transfected PHLFs after transforming growth factor-β1 (TGF-β1) induction (Fig. 3c, d), while a significant increase in myofibroblast markers was observed in ACP5-overexpressing
Summary
IPF is characterized by altered ACP5 expression. We first sought to examine the levels of ACP5 in the sera of IPF patients and control subjects. Expected, the expression of ACP5 was efficiently silenced or enhanced following ACP5 siRNA or ACP5-plasmid transfection (Supplementary Fig. 1a, b) Both Western blot and RTPCR analyses demonstrated that fibroblast differentiation to myofibroblast was abrogated in ACP5 siRNA-transfected PHLFs after TGF-β1 induction (Fig. 3c, d), while a significant increase in myofibroblast markers was observed in ACP5-overexpressing. The knockdown of ACP5 expression in PHLFs revealed lower levels of β-CATENIN following TGF-β1 induction compared to those in the group transfected with Scrambled siRNA (Fig. 4b). To confirm these results, the expression of ACP5 was enhanced in Acp5−/− PMLFs and PHLFs by plasmid transfection. Acp[5] deficiency blunted the increasing of β-catenin induced by BLM (Supplementary Fig. 4)
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