Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis

Srivastava, Mrigank; Steinwede, Kathrin; Kiviranta, Riku; Morko, Jukka; Hoymann, Heinz-Gerd; Länger, Florian; Bühling, Frank; Welte, Tobias; Maus, Ulrich A.

doi:10.1186/1465-9921-9-54

Cited by 54 publications

(53 citation statements)

References 35 publications

(47 reference statements)

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“…Many clade B SERPINs are inhibitors of cathepsin (G, S, K, L), which have a well-known monocyte/granulocyte chemoattractant function. [28][29][30] At this time, all our animals developed well evident interstitial lung fibrosis after BLM treatment, which was significantly more extensive in SERPIN B3 TG mice. This finding reinforces our previous data obtained from the study of IPF lung samples wherein more extensive fibrosis was observed in patients with higher SERPIN B3/B4 expression.…”

Section: Discussionmentioning

confidence: 98%

Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Lunardi

Villano

Perissinotto

et al. 2011

Laboratory Investigation

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SERPIN B3/B4, members of the serpin superfamily, are fundamental for the control of proteolysis through a known inhibitory function of different proteases. Several studies have documented an important role of SERPIN B3 in the modulation of inflammation, programmed cell death and fibrosis. To confirm the role of SERPIN B3 in lung fibrosis and overall investigate its influence on epithelial dysfunction, a stratified controlled trial randomly assigning bleomycin (BLM) treatment was performed on both SERPIN B3 transgenic (TG) and wild-type (WT) mice. TG and WT animals were killed 48 h (group T48 h) and 20 days (group T20d) after BLM treatment. Lung fibrosis was assessed by histology and hydroxyproline measurement. Architectural remodeling, inflammation, epithelial apoptosis and proliferation were quantified. Moreover, the profibrogenetic cytokine transforming growth factor (TGF)-b, cathepsin K, L and S were also investigated. No significant differences were observed between TG and WT mice of group T48 h in any parameters. In group T20d, less inflammation and a significant increase in epithelial proliferation were detected in treated TG than WT mice despite a similar apoptotic index, thus resulting in a different apoptosis/proliferation imbalance with a significant gain of epithelial proliferation. Moreover, TG mice showed higher TGF-b expression and more extended fibrosis. General linear model analysis, applied on morphological data, showed that interaction between SERPIN B3 expression and treatment was mainly significant for fibrosis. This study provides in vivo evidence for a role of SERPIN B3 in inhibiting inflammation and favoring epithelial proliferation with increased TGF-b secretion and thus the likelihood of consequent fibrogenesis.Laboratory Investigation (2011) 91, 945-954;

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Section: Discussionmentioning

confidence: 98%

Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Lunardi

Villano

Perissinotto

et al. 2011

Laboratory Investigation

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“…MMP-14 knockout mice accumulate collagen extracellularly in the soft tissues (69,92) and MMP-14 expression and activity is modulated by type I collagen (52,191). Cathepsin K knockout mice develop more severe bleomycin-induced fibrosis and transgenic mice overexpressing cathepsin K have an abrogated response to bleomycin-induced fibrosis (18,162). Additional support for an important role in ECM degradation comes from macrophage depletion studies.…”

Section: Extracellular Pathway Of Collagen Degradationmentioning

confidence: 99%

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

McKleroy

Lee

Atabai

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

191

169

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Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation. The increase in collagen degradation is critical in preventing the formation of permanent scar tissue each time the lung is exposed to injury. In pulmonary fibrosis, collagen degradation does not keep pace with collagen production, resulting in extracellular accumulation of fibrillar collagen. Collagen degradation occurs through both extracellular and intracellular pathways. The extracellular pathway involves cleavage of collagen fibrils by proteolytic enzyme including the metalloproteinases. The less-well-described intracellular pathway involves binding and uptake of collagen fragments by fibroblasts and macrophages for lysosomal degradation. The relationship between these two pathways and their relevance to the development of fibrosis is complex. Fibrosis in the lung, liver, and skin has been associated with an impaired degradative environment. Much of the current scientific effort in fibrosis is focused on understanding the pathways that regulate increased collagen production. However, recent reports suggest an important role for collagen turnover and degradation in regulating the severity of tissue fibrosis. The objective of this review is to evaluate the roles of the extracellular and intracellular collagen degradation pathways in the development of fibrosis and to examine whether pulmonary fibrosis can be viewed as a disease of impaired matrix degradation rather than a disease of increased matrix production.

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“…Fibroblasts-According to murine models of bleomycin-induced lung fibrosis (25,26,35) and liver fibrosis (20,36), several lines of evidence support that cysteine cathepsins may be involved in TGF-␤1-dependent myofibrogenesis and/or subsequent modulation of ECM (e.g. collagen and fibronectin) deposition.…”

Section: Characterization Of Cysteine Cathepsins Expressed By Ipfmentioning

confidence: 99%

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

Kasabova

Joulin-Giet

Lecaille

et al. 2014

Journal of Biological Chemistry

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Background: Proteolytic events are involved in the progression of lung fibrosis. Results: Cathepsin B participates in lung fibroblast differentiation by triggering TGF-␤1/Smad pathway. TGF-␤1 up-regulates secretion of cystatin C. Conclusion: TGF-␤1 promotes cystatin C-dependent inhibition of extracellular matrix-degrading cathepsins. Significance: Both cathepsin B and cystatin C could play a crucial role in fibrosis by favoring accumulation of ECM.

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Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis

Cited by 54 publications

References 35 publications

Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

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