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

BMC Research Notes

V Prasad Shastri¹  Jon Christensen¹ 

[1] BIOSS-Centre for Biological Signalling Studies, University of Freiburg, Schänzlestraße 18, Freiburg, 79104, Germany

关键词: Cancer therapy;    Bone resorption;    CTSK;    MMP-9 activation;    Enzyme activation;   

Others  :  1230915
DOI  :  10.1186/s13104-015-1284-8

 received in 2015-04-09, accepted in 2015-07-20,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Christensen and Shastri.

【 图 表 】

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