Cathepsin G-mediated activation of pro-matrix metalloproteinase 9 at the tumor-bone interface promotes transforming growth factor-beta signaling and bone destruction.
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.
Wilson
Thomas J
TJ
Department of Pathology and Microbiology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE 68198-5900, USA.
Nannuru
Kalyan C
KC
Singh
Rakesh K
RK
D000818:Animals; D001859:Bone Neoplasms / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D001842:Bone and Bones / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D056649:Cathepsin G / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D008324:Mammary Tumor Virus, Mouse; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010014:Osteolysis / Q000150:complications / Q000201:enzymology / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004792:Enzyme Precursors; D016376:Oligonucleotides, Antisense; D053245:RANK Ligand; D016212:Transforming Growth Factor beta; D056649:Cathepsin G; C120487:pro-matrix metalloproteinase 9; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9