GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine–threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in an in vivo mouse model of lung fibrosis and in vitro using different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFβ following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy.

FOXO4 peptide targets myofibroblast ameliorates bleomycin‐induced pulmonary fibrosis in mice through ECM‐receptor interaction pathway

“…Collagen degradation is mainly performed by matrix metalloproteinases(MMP) family, it has been reported that Mmp2, a major type IV collagen‐degradation enzyme, and its inhibitor Timp1 is increased in the lung tissues of BLM‐treated mice. 19 , 20 In our experiment, BLM induced a remarkable upregulation of Timp1 and Mmp2 mRNA and FOXO4‐DRI downregulated their expression similar to PFD group (Figure 1E ). These results suggest that FOXO4‐DRI represses collagen deposition to ameliorate BLM‐induced PF.…”

“…Apart from collagen deposition, the dysregulation of collagen degradation also contributes to the development of PF. Collagen degradation is mainly performed by matrix metalloproteinases(MMP) family, it has been reported that Mmp2, a major type IV collagen‐degradation enzyme, and its inhibitor Timp1 is increased in the lung tissues of BLM‐treated mice 19,20 . In our experiment, BLM induced a remarkable upregulation of Timp1 and Mmp2 mRNA and FOXO4‐DRI downregulated their expression similar to PFD group (Figure 1E).…”

Nordentatin Inhibits Neuroblastoma Cell Proliferation and Migration through Regulation of GSK-3 Pathway

“…Kitano et al [41] discovered that inhibiting GSK-3 expression could decrease cancer cell motility and invasion. The inhibition of GSK-3 regulates MMP-9 expression in various tissues [42]. It has been shown that the GSK-3 inhibitor SB216763 induces apoptosis by suppressing the NF-κB signaling pathway in osteosarcoma cells [43].…”

Immune Mechanisms of Pulmonary Fibrosis with Bleomycin

“…Two gelatinases, MMP-2 and MMP-9, are of particular interest because they can degrade type IV collagen and gelatin, which are major components of basement membranes. Cinetto et al reported that the levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were increased in the BALF of BLM-treated mice and that glycogen synthase 3 (GSK-3) inhibition may modulate MMP-2, MMP-9, TIMP-1, and TIMP-2 activity in BALF and lung tissue, thus preventing BLM-induced lung injury [ 93 ].…”