Matrix-metalloproteinase-9 is cleaved and activated by cathepsin K

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.

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.

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.