Osteoblast-derived MMP-2 impacts TGFβ activation and tumor survival in the <i>in vivo</i> tumor-bone microenvironment.

<p><b>A</b>, The levels of TGFβ in normalized tumor-bone lysates derived from WT and MMP-2^−/− tumor or sham injected tibias was assessed by ELISA. <b>B</b>, Representative immunoblots for phospho-SMAD (pSMAD2), total smad2 (SMAD2), phospho-AKT (pAKT), total AKT (AKT) and actin (loading control) in the tumor-bone lysates derived from WT and MMP-2^−/− mice. Densitometry on immunoblots generated from tumor bone lysates of at least 5 animals per group was used to generate graphs of the ratio of pSMAD2/SMAD2 and pAKT/AKT. Data are mean ± SD. *, p<0.05. <b>C</b>, Osteoblast derived MMP-2 controls TGFβ activation and mammary survival in the tumor-bone microenvironment. (<b>1</b>) Tumor derived signals induce osteoblast retraction from mineralized matrix and the resorption of the non-mineralized osteoid canopy. (<b>2</b>) We posit that MMP-2 processing of the factors that sequester TGFβ in a latent state such as LTBP-3 and LAP initiates TGFβ activation. (<b>3</b>) Our data show that the activation of TGFβ by osteoblast derived MMP-2 mediates tumor survival and we hypothesize this mini-vicious cycle is essential for the establishment of the traditional vicious cycle of tumor induced osteolysis.