Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis

ABSTRACT: Cavitation in tuberculosis (TB) enables highly efficient person-to-person aerosol transmission. Currently, a number of hypotheses exist regarding the mechanisms underlying this process. To explore this process, we undertook an unbiased next-generation transcriptional analysis of samples from cavity walls, grossly normal tissue from the same lung, and uninfected control lungs. Of 17,318 mapped host transcripts, only 199 showed a significant >2-fold change in cavity wall versus normal infected and uninfected samples. Amongst 22 upregulated proteases, 5 type I collagenases were over-represented; these included cathepsin K (CTSK), mast cell chymase-1 (CMA1), matrix metalloproteinase (MMP)-1, MMP-13, and MMP-14. To determine if cavitation was associated with changes in collagen turnover, we assayed serum and urinary markers of collagen metabolism in rabbits with cavitary TB versus infected controls. Serum collagen type 1 C-terminal propeptide (CICP, a marker of collagen synthesis and degradation) and urinary deoxypyridinoline (DPD, a marker of degradation) were increased by 10- (p = 0.019) and 4-fold (p = 0.068), respectively; while urinary helical peptide (a marker of degradation) was decreased 3-fold (p=0.015). This indicates that cavitation in TB is associated with significant increases of both destruction and synthesis of collagen and that cleavage of type I collagen occurs outside the known cleavage sites of MMP-1, -13 and -14. Rabbit gene expression analysis in lung tissue from M. tuberculosis infected animals. Cavitary tissue, non cavitary tissue and lung tissue from non-infected animals are compared.

ORGANISM(S): Oryctolagus cuniculus

SUBMITTER: Christer Larsson 

PROVIDER: E-GEOD-68206 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress