期刊
BIOLOGICAL CHEMISTRY
卷 393, 期 12, 页码 1391-1403出版社
WALTER DE GRUYTER GMBH
DOI: 10.1515/hsz-2012-0204
关键词
cysteine cathepsins; colon; intercellular junctions; intestinal barrier; mucus
资金
- Jacobs University Bremen [2140/90140]
- Deutsche Forschungsgemeinschaft (DFG) [BR 1308/10-1]
- Swedish Research Council [7461, 21027]
- Swedish Cancer Foundation
- Knut and Alice Wallenberg Foundation
- IngaBritt and Arne Lundberg Foundation
- Wilhelm and Martina Lundgren's Foundation
- Torsten och Ragnar Soderbergs Stiftelser
- Swedish Foundation for Strategic Research-The Mucus-Bacteria-Colitis Center (MBC) of the Innate Immunity Program
Cathepsin K has been shown to exhibit antimicrobial and anti-inflammatory activities in the mouse colon. To further elucidate its role, we used Ctsk(-/-) mice and demonstrated that the absence of cathepsin K was accompanied by elevated protein levels of related cysteine cathepsins (cathepsins B, L, and X) in the colon. In principle, such changes could result in altered subcellular localization; however, the trafficking of cysteine cathepsins was not affected in the colon of Ctsk(-/-) mice. However, cathepsin K deficiency affected the extracellular matrix constituents, as higher amounts of collagen IV and laminin were observed. Moreover, the localization pattern of the intercellular junction proteins E-cadherin and occludin was altered in the colon of Ctsk(-/-) mice, suggesting potential impairment of the barrier function. Thus, we used an ex vivo method for assessing the mucus layers and showed that the absence of cathepsin K had no influence on mucus organization and growth. The data of this study support the notion that cathepsin K contributes to intestinal homeostasis and tissue architecture, but the lack of cathepsin K activity is not expected to affect the mucus-depending barrier functions of the mouse colon. These results are important with regard to oral administration of cathepsin K inhibitors that are currently under investigation in clinical trials.
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