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

被引：103

作者：

Christensen J. ^{[1
,2
]}

Shastri V.P. ^{[1
,2
]}

机构：

[1] Institute for Macromolecular Chemistry, University of Freiburg, Hermann-Staudinger-Haus Stefan-Meier-Straße 31, Freiburg

[2] BIOSS-Centre for Biological Signalling Studies, University of Freiburg, Schänzlestraße 18, Freiburg

来源：

BMC Research Notes | / 8卷 / 1期

关键词：

Bone resorption; Cancer therapy; CTSK; Enzyme activation; MMP-9; activation;

D O I：

10.1186/s13104-015-1284-8

中图分类号：

学科分类号：

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. © 2015 Christensen and Shastri.

引用

共 37 条

[21]

Davis G.E., Pintar Allen K.A., Salazar R., Maxwell S.A., Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices, J Cell Sci, 114, pp. 917-930, (2001)

[22]

Zhao Y., Lyons C.E., Xiao A., Templeton D.J., Sang Q.A., Brew K., Et al., Urokinase directly activates matrix metalloproteinases-9: A potential role in glioblastoma invasion, Biochem Biophys Res Commun, 369, 4, pp. 1215-1220, (2008)

[23]

Ogata Y., Itoh Y., Nagase H., Steps involved in activation of the pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of metalloproteinases-1 complex by 4-aminophenylmercuric acetate and proteinases, J Biol Chem, 270, 31, pp. 18506-18511, (1995)

[24]

Shapiro S.D., Fliszar C.J., Broekelmann T.J., Mecham R.P., Senior R.M., Welgus H.G., Activation of the 92-kDa gelatinase by stromelysin and 4-aminophenylmercuric acetate. Differential processing and stabilization of the carboxyl-terminal domain by tissue inhibitor of metalloproteinases (TIMP), J Biol Chem, 270, 11, pp. 6351-6356, (1995)

[25]

Turk B., Turk D., Turk V., Lysosomal cysteine proteases: More than scavengers, Biochim Biophys Acta, 1477, 1-2, pp. 98-111, (2000)

[26]

Xia L., Kilb J., Wex H., Li Z., Lipyansky A., Breuil V., Et al., Localization of rat cathepsin K in osteoclasts and resorption pits: Inhibition of bone resorption and cathepsin K-activity by peptidyl vinyl sulfones, Biol Chem, 380, 6, pp. 679-687, (1999)

[27]

Drake F.H., Dodds R.A., James I.E., Connor J.R., Debouck C., Richardson S., Et al., Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts, J Biol Chem, 271, 21, pp. 12511-12516, (1996)

[28]

Hou W.S., Li W., Keyszer G., Weber E., Levy R., Klein M.J., Et al., Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium, Arthritis Rheum, 46, 3, pp. 663-674, (2002)

[29]

Littlewood-Evans A.J., Bilbe G., Bowler W.B., Farley D., Wlodarski B., Kokubo T., Et al., The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma, Cancer Res, 57, 23, pp. 5386-5390, (1997)

[30]

Littlewood-Evans A., Kokubo T., Ishibashi O., Inaoka T., Wlodarski B., Gallagher J.A., Et al., Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry, Bone, 20, 2, pp. 81-86, (1997)

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