Cathepsin G-mediated activation of pro-matrix metalloproteinase 9 at the tumor-bone interface promotes transforming growth factor-β signaling and bone destruction

Thomas J. Wilson, Kalyan C. Nannuru, Rakesh K. Singh

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Increased transforming growth factor-β (TGF-β) signaling has been observed at the tumor-bone interface of mammary tumor-induced osteolytic lesions despite no observed transcriptional up-regulation of TGF-β. To this point, the mechanism for enhanced TGF-β signaling remains unclear. The bulk of TGF-β that is released at the tumor-bone interface is in an inactive form secondary to association with β-latency-associated protein and latency TGF-β binding protein. We hypothesized that the observed increase in TGF-β signaling is due to increased cathepsin G-dependent, matrix metalloproteinase 9 (MMP9)-mediated activation of latent TGF-β. MMP9 is capable of activating latent TGF-β, and we observed that decreased production of MMP9 was associated with reduced TGF-β signaling. Similar to TGF-β, MMP9 is released in an inactive form and requires proteolytic activation. We showed that cathepsin G, which we have previously shown to be up-regulated at the tumor-bone interface, is capable of activating pro-MMP9. Inhibition of cathepsin G in vivo significantly reduced MMP9 activity, increased the ratio of latent TGF-β to active TGF-β, and reduced the level of TGF-β signaling. Our proposed model based on these results is that cathepsin G is up-regulated through tumor-stromal interactions and activates pro-MMP9, active MMP9 cleaves and releases active TGF-β, and active TGF-β can then promote tumor growth and enhance osteoclast activation and subsequent bone resorption. Thus, for the first time, we have identified cathepsin G and MMP9 as proteases involved in enhanced TGF-β signaling at the tumor-bone interface of mammary tumor-induced osteolytic lesions and have identified these proteases as potential therapeutic targets.

Original languageEnglish (US)
Pages (from-to)1224-1233
Number of pages10
JournalMolecular Cancer Research
Volume7
Issue number8
DOIs
StatePublished - Aug 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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