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

Abstract

Increased transforming growth factor-beta (TGF-beta) signaling has been observed at the tumor-bone interface of mammary tumor-induced osteolytic lesions despite no observed transcriptional up-regulation of TGF-beta. To this point, the mechanism for enhanced TGF-beta signaling remains unclear. The bulk of TGF-beta that is released at the tumor-bone interface is in an inactive form secondary to association with beta-latency-associated protein and latency TGF-beta binding protein. We hypothesized that the observed increase in TGF-beta signaling is due to increased cathepsin G-dependent, matrix metalloproteinase 9 (MMP9)-mediated activation of latent TGF-beta. MMP9 is capable of activating latent TGF-beta, and we observed that decreased production of MMP9 was associated with reduced TGF-beta signaling. Similar to TGF-beta, 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-beta to active TGF-beta, and reduced the level of TGF-beta 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-beta, and active TGF-beta 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-beta signaling at the tumor-bone interface of mammary tumor-induced osteolytic lesions and have identified these proteases as potential therapeutic targets.

• Authors: Thomas J Wilson, Kalyan C Nannuru, Rakesh K Singh
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 7 Issue 8 Pg. 1224-33 (Aug 2009) ISSN: 1557-3125 [Electronic] United States
• PMID: 19671689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Precursors
• Oligonucleotides, Antisense
• RANK Ligand
• Transforming Growth Factor beta
• Cathepsin G
• pro-matrix metalloproteinase 9
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Bone Neoplasms (complications, enzymology, pathology)
• Bone and Bones (drug effects, enzymology, pathology)
• Cathepsin G (antagonists & inhibitors, metabolism)
• Enzyme Activation (drug effects)
• Enzyme Precursors (metabolism)
• Mammary Tumor Virus, Mouse
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Oligonucleotides, Antisense (pharmacology)
• Osteolysis (complications, enzymology, pathology)
• RANK Ligand (metabolism)
• Signal Transduction (drug effects)
• Transforming Growth Factor beta (metabolism)