Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice.

Abstract

OBJECTIVE:

Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation.

DESIGN:

Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk(-/-) mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples.

RESULTS:

Using Ctsk(-/-) mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk(-/-) mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk(-/-) mice ameliorates the severity of intestinal inflammation.

CONCLUSION:

These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.

• Authors: Christian Sina, Simone Lipinski, Olga Gavrilova, Konrad Aden, Ateequr Rehman, Andreas Till, Andrea Rittger, Rainer Podschun, Ulf Meyer-Hoffert, Robert Haesler, Emilie Midtling, Katrin Pütsep, Michael A McGuckin, Stefan Schreiber, Paul Saftig, Philip Rosenstiel
• Journal: Gut (Gut) Vol. 62 Issue 4 Pg. 520-30 (Apr 2013) ISSN: 1468-3288 [Electronic] England
• PMID: 22442160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dextran Sulfate
• Cathepsin K

Topics

• Animals
• Blotting, Western
• Cathepsin K (metabolism, pharmacology)
• Colitis (chemically induced, drug therapy, microbiology, pathology)
• Dextran Sulfate
• Disease Models, Animal
• Endoscopy, Gastrointestinal
• Enzyme-Linked Immunosorbent Assay
• Immunohistochemistry
• Mice
• Mice, Inbred C57BL
• Real-Time Polymerase Chain Reaction