title: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, Kiel D-24105, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
authors.forename: Simone
authors.initials: S
authors.lastname: Lipinski
authors.forename: Olga
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Konrad
authors.initials: K
authors.lastname: Aden
authors.forename: Ateequr
authors.initials: A
authors.lastname: Rehman
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Andrea
authors.initials: A
authors.lastname: Rittger
authors.forename: Rainer
authors.initials: R
authors.lastname: Podschun
authors.forename: Ulf
authors.initials: U
authors.lastname: Meyer-Hoffert
authors.forename: Robert
authors.initials: R
authors.lastname: Haesler
authors.forename: Emilie
authors.initials: E
authors.lastname: Midtling
authors.forename: Katrin
authors.initials: K
authors.lastname: Pütsep
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056657:Cathepsin K / Q000378:metabolism / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000382:microbiology* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D016099:Endoscopy, Gastrointestinal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016264:Dextran Sulfate; D056657:Cathepsin K