Complete degradation of type X collagen requires the combined action of interstitial collagenase and osteoclast-derived cathepsin-B.

Sires, Ulrike I.; Schmid, Thomas; Fliszar, Catherine J.; Wang, Zhiqiang; Gluck, Stephen L.; Welgus, Howard G.

doi:10.1172/jci117896

Cited by 37 publications

(12 citation statements)

References 41 publications

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“…In fact, cathepsins K, L, and S are among the most potent elastases known [1]. In vitro , cathepsin B reportedly degrades collagen type IV and X and fibronectin [17,18]. Cathepsins L, S, and K degrade fibrillar collagens [19], fibronectin, and laminin, and DPPI cleaves fibronectin and collagens type I, III, and IV [20].…”

Section: Matrix Remodeling By Cathepsinsmentioning

confidence: 99%

Importance of lysosomal cysteine proteases in lung disease

Wolters

Chapman

2000

Respir Res

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The human lysosomal cysteine proteases are a family of 11 proteases whose members include cathepsins B, C, H, L, and S. The biology of these proteases was largely ignored for decades because of their lysosomal location and the belief that their function was limited to the terminal degradation of proteins. In the past 10 years, this view has changed as these proteases have been found to have specific functions within cells. This review highlights some of these functions, specifically their roles in matrix remodeling and in regulating the immune response, and their relationship to lung diseases.

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Section: Matrix Remodeling By Cathepsinsmentioning

confidence: 99%

Importance of lysosomal cysteine proteases in lung disease

Wolters

Chapman

2000

Respir Res

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“…[8][9][10][11][12][13][14] The activity of cysteine proteinases is generally dependent on pH values below 7, as found in lysosomes and specific extracellular locations. 15 Over the years, several different cysteine cathepsins have been suggested to participate in osteoarthritic cartilage destruction.…”

mentioning

confidence: 99%

Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis

Morko

Söderström²,

Säämänen³

et al. 2004

Annals of the Rheumatic Diseases

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Objectives: To study the expression of cysteine proteinases, particularly cathepsin K, and their extracellular inhibitor cystatin C in articular cartilage of transgenic Del1 mice which harbour a short deletion mutation in a type II collagen transgene and are predisposed to early onset osteoarthritis. Methods: Northern analysis was used to measure mRNA levels of cathepsins B, H, K, L, and S, and cystatin C in total RNA extracted from knee joints of Del1 mice, using their non-transgenic litter mates as controls. Immunohistochemistry and morphometry was used to study the distribution of cathepsin K and cystatin C in the knee joints. Results: Up regulation of cathepsin K mRNA expression was seen in the knee joints of transgenic Del1 mice at the onset of cartilage degeneration. Cathepsin K was found near sites of matrix destruction in articular chondrocytes, particularly in clusters of proliferating cells, and in calcified cartilaginous matrix. In intact articular cartilage of control animals, cathepsin K was only seen in a small number of chondrocytes. Upon aging, control animals also developed osteoarthritis, which was accompanied by increased cathepsin K expression. Cystatin C was mostly localised in and around chondrocytes located in calcified cartilage, with no obvious association with the onset of cartilage degeneration. Conclusion: The temporospatial distribution of cathepsin K in osteoarthritic cartilage suggests a role for this enzyme in the pathogenesis of osteoarthritis. Because cathepsin K can digest cartilage matrix components it may contribute to the development of osteoarthritic lesions. These data may provide new clues for the development of treatments aimed at preventing cartilage degeneration.

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“…Cathepsin B is a cysteinyl protease that is expressed ubiquitously in lung tissue, particularly in bronchial epithelial cells and macrophages 10. Cathepsin B degrades types IV and X collagen and also fibronectin in vitro,11 12 and intratracheal instillation of cathepsin B has been shown to induce emphysema in hamsters 13. Cathepsin B activity is also increased in infective and inflammatory conditions such as pneumonia and cystic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro

Geraghty

Rogan

Greene

et al. 2008

Thorax

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Background: Neutrophil elastase (NE) activity is increased in lung diseases such as a 1 -antitrypsin (A1AT) deficiency and pneumonia. It has recently been shown to induce expression of cathepsin B and matrix metalloprotease 2 (MMP-2) in vitro and in a mouse model. It is postulated that increased cathepsin B and MMP-2 in acute and chronic lung diseases result from high levels of extracellular NE and that expression of these proteases could be inhibited by A1AT augmentation therapy. Methods: Cathepsin and MMP activities were assessed in bronchoalveolar lavage (BAL) fluid from patients with A1AT deficiency, pneumonia and control subjects. Macrophages were exposed to BAL fluid rich in free NE from patients with pneumonia following pretreatment with A1AT. MMP-2, cathepsin B, secretory leucoprotease inhibitor (SLPI) and lactoferrin levels were determined in BAL fluid from A1AT-deficient patients before and after aerosolisation of A1AT. Results: BAL fluid from both patients with pneumonia and those with A1AT deficiency containing free NE had increased cathepsin B and MMP-2 activities compared with BAL fluid from healthy volunteers. The addition of A1AT to BAL fluid from patients with pneumonia greatly reduced NE-induced cathepsin B and MMP-2 expression in macrophages in vitro. A1AT augmentation therapy to A1AT-deficient individuals also reduced cathepsin B and MMP-2 activity in BAL fluid in vivo. Furthermore, A1AT-deficient patients had higher levels of SLPI and lactoferrin after A1AT augmentation therapy. Conclusion: These findings suggest a novel role for A1AT inhibition of NE-induced upregulation of MMP and cathepsin expression both in vitro and in vivo.Raised levels of proteases are typically observed in acute and chronic lung diseases at sites of inflammation and infection. Proteases have a number of effects including tissue destruction, tissue remodelling and cleavage of soluble innate factors. We have previously shown that cathepsin B can cleave and inactivate key innate immunity proteins including lactoferrin 1 and secretory leucoprotease inhibitor (SLPI).2 We have also recently described a novel hierarchy in protease regulation which showed that neutrophil elastase (NE) can induce the expression of cathepsin B and matrix metalloprotease 2 (MMP-2) in vitro and in a mouse model.3 MMPs and cathepsins have previously been found, together with NE, in conditions such as emphysema and cystic fibrosis.4 5 We postulated that increased extracellular NE activity in vivo may induce expression of both cathepsins and MMPs. These proteases are capable of significant tissue destruction and inflammation, both directly and indirectly by cleaving key innate anti-inflammatory and antimicrobial proteins. We hypothesised that NE-mediated upregulation of cathepsins and MMPs could be inhibited by a 1 -antitrypsin (A1AT), a naturally occurring inhibitor of NE. Reduced expression of these destructive proteases could have significant implications in reducing both lung inflammation and cleavage of innate immunity proteins.In thi...

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Complete degradation of type X collagen requires the combined action of interstitial collagenase and osteoclast-derived cathepsin-B.

Cited by 37 publications

References 41 publications

Importance of lysosomal cysteine proteases in lung disease

Importance of lysosomal cysteine proteases in lung disease

Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis

Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro

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