Effects of cathepsin K deficiency on intercellular junction proteins, luminal mucus layers, and extracellular matrix constituents in the mouse colon

Biol Chem. 2012 Dec;393(12):1391-403. doi: 10.1515/hsz-2012-0204.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / analysis
  • Cadherins / metabolism
  • Cathepsin B / metabolism
  • Cathepsin K / genetics*
  • Cathepsin K / metabolism
  • Cathepsin L / metabolism
  • Colon / metabolism*
  • Colon / ultrastructure
  • Extracellular Matrix / metabolism*
  • Gene Deletion
  • Intercellular Junctions / metabolism*
  • Intercellular Junctions / ultrastructure
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / ultrastructure
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Occludin / analysis
  • Occludin / metabolism
  • Proteolysis

Substances

  • Cadherins
  • Occludin
  • Cathepsin B
  • Cathepsin L
  • Cathepsin K