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

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.

Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Faslpr Mice

“…3D, 3H) or via other proteolytic enzymes (14, 48). Several lines of evidence demonstrated that deficiency of CatK (13, 14, 49) or other cathepsins (48, 50) altered the expression of other proteins. Such a role of CatK may not simply relate to its proteolytic activity, a longstanding question that has still remained unanswered.…”

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

“…However, the main focus of research was for a long time on the ubiquitously expressed cathepsins B, D, and L. In contrast, the cysteine cathepsins K and S gained attention only more recently (Arampatzidou et al 2012;Dauth et al 2012;Driessen et al 1999;Friedrichs et al 2003;Muller et al 2014;Pierre and Mellman 1998;Tamhane et al 2014;Tepel et al 2000). This is because of their cell type-specific expression and vital functions, for instance, in the pericellular space (resorption lacuna) of osteoclasts or in the extracellular space Fig.…”

“…An example where cysteine cathepsins cleave extracellular matrix components like collagen IV under physiological conditions at neutral pH is seen by epidermal keratinocytes which secrete cathepsin B upon mechanical scratch wounding for ECM degradation to ease keratinocyte migration for wound healing and tissue regeneration (Buth et al 2007). Another example is provided by investigations on the gastro-intestinal tract, where cysteine cathepsins resume functions in the extracellular space of the mucosa during tissue regeneration from mechanical trauma, or where cysteine cathepsins are active even at the gut lumen-exposed apical side of the mucosal wall (Arampatzidou et al 2012;Mayer et al 2009;Tamhane et al 2014;Vreemann et al 2009). A striking and well-studied example in which cysteine cathepsins are active for a prolonged time on one of their natural targets under non-favorable conditions is realized in the thyroid gland, where cathepsins B, K, L, and S process thyroglobulin differently depending on the conditions encountered (Brix et al 1996(Brix et al , 2001Tepel et al 2000;Friedrichs et al 2003; Jordans et al 2009).…”

“…Furthermore, recent understanding of protease functions also includes numerous roles in cellular signaling, thus adding even further to the complexity (Turk and Stoka 2007). To study proteases in specific cellular contexts was the next step that addressed protease activities in different cell types, tissues, or animal models (Akkari et al 2014;Arampatzidou et al 2012;Chan et al 2009;Dauth et al 2011b;Friedrichs et al 2003;Gansz et al 2013;Nakagawa and Rudensky 1999;Reinheckel et al 2001;Sevenich et al 2014;Tamhane et al 2014). Understanding proteolysis in a larger context now includes focusing on the genes encoding proteolytic enzymes including transcriptional and translational regulation (Reiser et al 2010).…”

Secondary biochemical and morphological consequences in lysosomal storage diseases

“…It is noteworthy that neur aminidase I is a negative regulator of lysosomal exocyto sis, and its deficiency results in increased lysosomal exo cytosis [87]. In cathepsin K deficient mice, alterations in the architecture of colonic enterocytes and the localiza tion of E cadherin and occluding were observed [88].…”