title: Matrix-metalloproteinase-9 is cleaved and activated by cathepsin K.
abstract: BACKGROUND
  Matrix-metalloproteinases 9 (MMP-9) belongs to the class of matrix metalloproteinases whose main function is to degrade and remodel the extracellular matrix (ECM). MMP-9 has been shown to be an integral part of many diseases where modulation of the ECM is a key step such as cancer, osteoporosis and fibrosis. MMP-9 is secreted as a latent pro-enzyme that requires activation in the extracellular space. Therefore, identifying physiological and molecular contexts, which can activate MMP-9 is important.
  
  
  RESULTS
  Acidification of osteoclast-conditioned media to pH 5 resulted in a fragment with a size corresponding to active MMP-9. Also, treatment of recombinant proMMP-9 with recombinant cathepsin K (CTSK) at pH 5 yielded a fragment that corresponded to the molecular weight of active MMP-9, and showed MMP-9 activity. This activation was abrogated in the presence of CTSK inhibitor indicating that CTSK was responsible for the activation of pro-MMP-9. Knocking down CTSK in MDA-MB-231 cells also diminished MMP-9 activity compared to wild type control.
  
  
  CONCLUSIONS
  Here we provide the first evidence that CTSK can cleave and activate MMP-9 in acidic environments such as seen in tumors and during bone resorption. This finding provides a key link between CTSK expression in tumors and bone and ECM remodeling, through MMP-9 activation. This novel mechanism to activate MMP-9 through extracellular physiological changes elucidated in this study reveals a protease-signaling network involving CTSK and MMP-9 and provides the impetus to explore ECM proteases as physiological markers and pharmacological targets.
authors.affiliation: Institute for Macromolecular Chemistry, University of Freiburg, Hermann-Staudinger-Haus Stefan-Meier-Straße 31, 79104, Freiburg, Germany. jonchris@mail.com.|BIOSS-Centre for Biological Signalling Studies, University of Freiburg, Schänzlestraße 18, 79104, Freiburg, Germany. jonchris@mail.com.
authors.forename: Jon
authors.initials: J
authors.lastname: Christensen
authors.affiliation: Institute for Macromolecular Chemistry, University of Freiburg, Hermann-Staudinger-Haus Stefan-Meier-Straße 31, 79104, Freiburg, Germany. prasad.shastri@gmail.com.|BIOSS-Centre for Biological Signalling Studies, University of Freiburg, Schänzlestraße 18, 79104, Freiburg, Germany. prasad.shastri@gmail.com.
authors.forename: V Prasad
authors.initials: VP
authors.lastname: Shastri
mesh_terms: D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology*; D005110:Extracellular Space / Q000737:chemistry / Q000201:enzymology*; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004792:Enzyme Precursors; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D056657:Cathepsin K; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9