BACKGROUND. Osteoblastic bone metastasis is the predominant phenotype observed in prostatecancerpatientsandisassociatedwithhighpatientmortalityandmorbidity.However,the mechanisms determining the development of this phenotype are not well understood. Prostate cancer cells secrete several osteogenic factors including Wnt proteins, which are not only osteoinductive but also oncogenic. Therefore, the purpose of the study was to investigate the contribution of the Wnt signaling pathway in prostate cancer growth, incidence of bone metastases, and osteoblastic phenotype of bone metastases. The strategy involved overexpressing the Wnt antagonist, DKK-1, in the mixed osteoblastic and osteolytic Ace-1 prostate cancer cells. METHODS. Ace-1prostatecancercellsstablyexpressinghumanDKK-1oremptyvectorwere established and transduced with lentiviral yellow fluorescent protein (YFP)-luciferase (Luc). The Ace-1/vector YFP-LUC and Ace-1/DKK-1 YFP-LUC cells were injected subcutaneously, intratibially, or in the left cardiac ventricle in athymic mice. RESULTS. Unexpectedly, DKK-1significantly increased Ace-1 subcutaneoustumor massand the incidence of bone metastases after intracardiac injection of Ace-1 cells. DKK-1 increased Ace-1 tumor growth associated with increased phospho46 c-Jun amino-terminal kinase by the Wntnoncanonicalpathway.Asexpected,DKK-1decreasedtheAce-1osteoblasticphenotypeof bone metastases, as confirmed by radiographic, histopathologic, and microcomputed tomographic analysis. DKK-1 decreased osteoblastic activity via the Wnt canonical pathway evidenced by an inhibition of T-cell factor activity in murine osteoblast precursor ST2 cells. CONCLUSION. The present study showed that DKK-1 is a potent inhibitor of bone growth in prostate cancer-induced osteoblastic metastases. Prostate 71: 615–625, 2011. # 2010 Wiley-Liss, Inc.