title: Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases.
abstract: Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the receptor activator of nuclear factor κ-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Coculture of PCa cells with MC3T3 preosteoblasts also revealed a role for secretory PAP in OB-PCa cross talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCa cells in OB bone metastases increases OPG and plays a critical role in the vicious cross talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa OB bone lesions.
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Alexander
authors: A
authors: Kirschenbaum
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Sudeh
authors: S
authors: Izadmehr
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Shen
authors: S
authors: Yao
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Kieley L
authors: KL
authors: O'Connor-Chapman
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Alan
authors: A
authors: Huang
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Elias M
authors: EM
authors: Gregoriades
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Shoshana
authors: S
authors: Yakar
authors: Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.
authors: Alice C
authors: AC
authors: Levine
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D034741:RNA, Small Interfering; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase