Abstract 2464: Novel MMP-3 generated PTHrP peptides promote osteoblast proliferation: Implications for prostate to bone metastases

Abstract

Abstract Up to 90% of patients that succumb to prostate cancer will have evidence of bone metastasis. Prostate to bone metastases generate mixed lesions hallmarked by areas of extensive bone resorption and formation mediated by osteoclasts and osteoblasts respectively. Tumor derived PTHrP has been defined as a major molecule facilitating tumor-osteoblast interaction. Mature PTHrP is comprised of 36 amino-acids and new data from our lab has identified that MMP-3, one of several MMPs we have found highly expressed in the prostate cancer-bone microenvironment, can process PTHrP to yield novel distinct peptides. We posit that MMP-3 generated PTHrP peptides can have distinct biological effects on osteoblasts. Our results to date demonstrate that MMP-3 processes mature PTHrP to yield PTHrP1-16, PTHrP17-26, and PTHrP27-36 amino acid peptides in vitro as determined by N-terminal amino acid sequencing and MALDI-TOF analysis. Next, we determined the biological activity of the MMP-3 generated PTHrP peptides by treating osteoblast cell lines and examining differentiation and proliferation. We found using alizarin red staining that the MMP-3 generated PTHrP peptides did not impact osteoblast differentiation. However, analysis of cell proliferation, using an MTT assay, identified that the PTHrP1-16 peptide stimulated osteoblast proliferation over a 24-hour period. Follow-up studies revealed that the MMP-3 generated PTHrP1-16 fragment significantly enhanced phosphorylation of MAPK 42/44 and CREB, presumably via the PTHrP receptor, PTH1R. In conclusion, our data identify for the first time that PTHrP is an MMP substrate and that MMP-3 generated PTHrP peptide PTHrP1-16, can promote osteoblast proliferation. These findings suggest that MMP-3 expression in the prostate tumor microenvironment can potentially impact osteoblast expansion and may play a role in the generation of osteoblastic lesions that are commonly associated with prostate to bone metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2464. doi:1538-7445.AM2012-2464