title: Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis.
abstract: Cavitation in tuberculosis enables highly efficient person-to-person aerosol transmission. We performed transcriptomics in the rabbit cavitary tuberculosis model. Among 17 318 transcripts, we identified 22 upregulated proteases. Five type I collagenases were overrepresented: cathepsin K (CTSK), mast cell chymase-1 (CMA1), matrix metalloproteinase 1 (MMP-1), MMP-13, and MMP-14. Studies of collagen turnover markers, specifically, collagen type I C-terminal propeptide (CICP), urinary deoxypyridinoline (DPD), and urinary helical peptide, revealed that cavitation in tuberculosis leads to both type I collagen destruction and synthesis and that proteases other than MMP-1, MMP-13, and MMP-14 are involved, suggesting a key role for CTSK. We confirmed the importance of CTSK upregulation in human lung specimens, using immunohistochemical analysis, which revealed perigranulomatous staining for CTSK, and we showed that CTSK levels were increased in the serum of patients with tuberculosis, compared with those in controls (3.3 vs 0.3 ng/mL; P = .005).
authors.affiliation: Infectious Diseases and Immunity, Imperial College London Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: Andre
authors.initials: A
authors.lastname: Kubler
authors.affiliation: Department of Molecular Biology, Umeå University, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: Brian
authors.initials: B
authors.lastname: Luna
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: Amaral
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: Michael
authors.initials: M
authors.lastname: Urbanowski
authors.affiliation: Infectious Diseases Pathogenesis Section, Comparative Medicine Branch, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Marlene
authors.initials: M
authors.lastname: Orandle
authors.affiliation: Infectious Diseases Pathogenesis Section, Comparative Medicine Branch, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bock
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: Laurene S
authors.initials: LS
authors.lastname: Cheung
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Winglee
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: Marc
authors.initials: M
authors.lastname: Halushka
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, South Korea.
authors.forename: Jin Kyun
authors.initials: JK
authors.lastname: Park
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.affiliation: Infectious Diseases and Immunity, Imperial College London.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
authors.affiliation: Infectious Diseases and Immunity, Imperial College London Faculty of Medicine, University of Southampton, United Kingdom.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000818:Animals; D056657:Cathepsin K / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology*; D011817:Rabbits; D014397:Tuberculosis, Pulmonary / Q000473:pathology*
chemical_list: D003094:Collagen; D056657:Cathepsin K; D017364:Collagenases
keywords: RNAseq; cathepsin K; collagen; collagenolysis; rabbit; tuberculosis