A recent study by Dr. Sime group demonstrated that ECM cross-linking enzyme transglutaminase 2 (TG2) plays a key role in fibrogenesis. It would be interesting to see if TG2 can be an effective therapeutic target.
In an editorial, Dr. Kolb and Dr. Gauldie suggested that targeting ECM cross-linking enzymes, NOT early mechanisms, would make sense to curb fibrosis.
In an editorial, Dr. Kolb and Dr. Gauldie suggested that targeting ECM cross-linking enzymes, NOT early mechanisms, would make sense to curb fibrosis.
Bleomycin --> TGFbeta --> TG2 --> ECM x-linking --> fibrosis
Am J Respir Crit Care Med. 2011 Jun 30. [Epub ahead of print]
Transglutaminase 2 and its Role in Pulmonary Fibrosis.
Olsen KC, Sapinoro RE, Kottmann RM, Kulkarni AA, Iismaa SE, Johnson GV, Thatcher TH, Phipps RP, Sime PJ.
Source
Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States; Lung Biology and Disease Program, University of Rochester, Rochester, New York, United States.
Abstract
RATIONALE:
Idiopathic pulmonary fibrosis is a deadly progressive disease with few treatment options. Transglutaminase 2 is a multifunctional protein but its function in pulmonary fibrosis is unknown.
OBJECTIVE:
To determine the role of transglutaminase 2 in pulmonary fibrosis.
METHODS:
The fibrotic response to bleomycin was compared between wild-type and transglutaminase 2 knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin fixed human lung biopsy sections by immunohistochemistry from patients with idiopathic pulmonary fibrosis. In addition, primary human lung fibroblasts were used to study transglutaminase 2 function in vitro.
MEASUREMENTS AND MAIN RESULTS:
Transglutaminase 2 knockout mice developed significantly reduced fibrosis compared to wild-type mice as determined by hydroxyproline content and histologic fibrosis score (p<0.05). Transglutaminase 2 expression and activity is increased in lung biopsy sections in humans with idiopathic pulomanary fibrosis compared with normal controls. In vitro over-expression of transglutaminase 2 led to increased fibronectin deposition while transglutaminase knockdown led to defects in contraction and adhesion. The pro-fibrotic cytokine TGF-β causes an increase in membrane-localized transglutaminase 2, increasing its enzymatic activity.
CONCLUSIONS:
Transglutaminase 2 is involved in pulmonary fibrosis in a mouse model and in human disease and is important in normal fibroblast function. With continued research on transglutaminase 2, it may offer a new therapeutic target.
PMID: 21700912 [PubMed - as supplied by publisher]
Transglutaminase 2 and its Role in Pulmonary Fibrosis.
Olsen KC, Sapinoro RE, Kottmann RM, Kulkarni AA, Iismaa SE, Johnson GV, Thatcher TH, Phipps RP, Sime PJ.
Source
Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States; Lung Biology and Disease Program, University of Rochester, Rochester, New York, United States.
Abstract
RATIONALE:
Idiopathic pulmonary fibrosis is a deadly progressive disease with few treatment options. Transglutaminase 2 is a multifunctional protein but its function in pulmonary fibrosis is unknown.
OBJECTIVE:
To determine the role of transglutaminase 2 in pulmonary fibrosis.
METHODS:
The fibrotic response to bleomycin was compared between wild-type and transglutaminase 2 knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin fixed human lung biopsy sections by immunohistochemistry from patients with idiopathic pulmonary fibrosis. In addition, primary human lung fibroblasts were used to study transglutaminase 2 function in vitro.
MEASUREMENTS AND MAIN RESULTS:
Transglutaminase 2 knockout mice developed significantly reduced fibrosis compared to wild-type mice as determined by hydroxyproline content and histologic fibrosis score (p<0.05). Transglutaminase 2 expression and activity is increased in lung biopsy sections in humans with idiopathic pulomanary fibrosis compared with normal controls. In vitro over-expression of transglutaminase 2 led to increased fibronectin deposition while transglutaminase knockdown led to defects in contraction and adhesion. The pro-fibrotic cytokine TGF-β causes an increase in membrane-localized transglutaminase 2, increasing its enzymatic activity.
CONCLUSIONS:
Transglutaminase 2 is involved in pulmonary fibrosis in a mouse model and in human disease and is important in normal fibroblast function. With continued research on transglutaminase 2, it may offer a new therapeutic target.
PMID: 21700912 [PubMed - as supplied by publisher]
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