title: Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism.
abstract: Prostate cancer frequently metastasizes to bone where it forms osteoblastic lesions through unknown mechanisms. Bone morphogenetic proteins (BMP) are mediators of skeletal formation. Prostate cancer produces a variety of BMPs, including BMP-6. We tested the hypothesis that BMP-6 contributes to prostate cancer-induced osteosclerosis at bone metastatic sites. Prostate cancer cells and clinical tissues produced BMP-6 that increased with aggressiveness of the tumor. Prostate cancer-conditioned medium induced SMAD phosphorylation in the preosteoblast MC3T3 cells, and phosphorylation was diminished by anti-BMP-6 antibody. Prostate cancer-conditioned medium induced mineralization of MC3T3 cells, which was blocked by both the BMP inhibitor noggin and anti-BMP-6. Human fetal bones were implanted in severe combined immunodeficient mice and after 4 weeks, LuCaP 23.1 prostate cancer cells were injected both s.c. and into the bone implants. Anti-BMP-6 or isotype antibody administration was then initiated. Anti-BMP-6 reduced LuCaP 23.1-induced osteoblastic activity, but had no effect on its osteolytic activity. This was associated with increased osteoblast numbers and osteoblast activity based on bone histomorphometric evaluation. As endothelin-1 has been implicated in bone metastases, we measured serum endothelin-1 levels but found they were not different among the treatment groups. In addition to decreased bone production, anti-BMP-6 reduced intraosseous, but not s.c., tumor size. We found that BMP-2, BMP-4, BMP-6, and BMP-7 had no direct effect on prostate cancer cell growth, but BMP-2 and BMP-6 increased the in vitro invasive ability of prostate cancer cell. These data show that prostate cancer promotes osteoblastic activity through BMP-6 and that, in addition to its bone effects, suggest that BMPs promote the ability of the prostate cancer cells to invade the bone microenvironment.
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109-0940, USA.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.forename: Jill
authors.initials: J
authors.lastname: Keller
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
mesh_terms: D000818:Animals; D001846:Bone Development; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001859:Bone Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D019332:Endothelin-1 / Q000097:blood; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051785:Smad Proteins / Q000378:metabolism
chemical_list: C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D019332:Endothelin-1; D051785:Smad Proteins