after intra-tibial tumor cells injection. This model may be useful to study cellular and molecular mechanisms that differ between androgen-dependent and androgen-independent prostate carcinomas when they metastasize to bone. In prostate cancer, androgen blockade strategies are usually used to treat osteoblastic bone metastases. However, responses to these therapies are often brief due to post-traductional modifications or mutations of AR that reduce ligand binding and inevitably lead to CRPC. The role of AR pathway in the osteoblastic progression of prostate cancer is poorly understood because available models of mixed and pure osteoblastic lesions are mainly androgen responsive like. Consequently, an active AR pathway is believed to be implicated in the osteoblastic progression of prostate cancer. However, concerning our PC3c model, this assumption does not occur as both cells lines PC3 and PC3c cell lines do not express AR. On the other side, AR negative models commonly used as PC3 and DU145 cells that derived from CRPC patients induced pure osteolytic lesions and do not reproduce what it is observed in clinic. Then, in order to meet the need for clinically relevant models of prostate cancer-associated bone lesions, more recent hormone-independent models have been developed like MDA PCa 118 and Ace-1 that similarly to the PC3c model do not express AR and induce mixed lesions. Nevertheless, osteogenesis that was induced by FGF-9 in the MDA PCa 118 model was not implicated in the osteoblastic response induced by PC3c as FGF-9 expression was not statistically significantly modulated between PC3 and PC3c cells. Interestingly, when compared with PC3, PC3c cells highly expressed ET-1, a mitogenic factor for OB. ET-1 is known to contribute to osteoblastic progression of prostate cancer cells by stimulating OB proliferation through the negative regulation of the 345627-80-7 chemical information inhibitor of the Wnt signaling, DKK1 which may explain, at least in part, the decrease of DKK1 observed in PC3c cells. Moreover, a decrease of DKK1 serum level in patients with advanced prostate cancer has been reported to be associated with occurrence of osteoblastic lesions which suggests that DKK1 inhibition in PC3c cells may contribute to the osteoblastic phenotype induced by these cells. BMPs have also been implicated in the formation of new bone induced by prostate cancer and the inhibition of BMPs by their inhibitor Noggin in C4-2B cells induces a decrease in the osteoblastic response, suggesting that the low expression level of Noggin in PC3c cells compared with PC3 cells may also contribute to the osteoblastic lesions induced by PC3c cells. Finally the over-expression of OPG may also contribute to the osteoblastic response induced by PC3c cells by limiting 9 New Androgen-Resistant Bone Metastasis Model OC differentiation. Based on OC and OB in vitro assay and TRAP staining in vivo, it appears that PC3c cells can also over stimulate osteoclastogenesis directly by acting on OC precursors and indirectly by increasing the RANKL/OPG ratio by OBs conducting to a general bone remodeling stimulation. On the other side, the RANKL/OPG ratio was not modulated by osteocytes like 19147858 MLO-Y4 cells. Concerning osteocyte involvement into prostate cancer progression in bone, we found that the expression of 10355733 SOST, an inhibitor of Wnt signaling, was induced by PC3 cells conditioned medium, suggesting a direct effect of osteocytes on OB differentiation during tumor bone progression. Meanwhile the expafter intra-tibial tumor cells injection. This model may be useful to study cellular and molecular mechanisms that differ between androgen-dependent and androgen-independent prostate carcinomas when they metastasize to bone. In prostate cancer, androgen blockade strategies are usually used to treat osteoblastic bone metastases. However, responses to these therapies are often brief due to post-traductional modifications or mutations of AR that reduce ligand 19232718 binding and inevitably lead to CRPC. The role of AR pathway in the osteoblastic progression of prostate cancer is poorly understood because available models of mixed and pure osteoblastic lesions are mainly androgen responsive like. Consequently, an 18083779 active AR pathway is believed to be implicated in the osteoblastic progression of prostate cancer. However, concerning our PC3c model, this assumption does not occur as both cells lines PC3 and PC3c cell lines do not express AR. On the other side, AR negative models commonly used as PC3 and DU145 cells that derived from CRPC patients induced pure osteolytic lesions and do not reproduce what it is observed in clinic. Then, in order to meet the need for clinically relevant models of prostate cancer-associated bone lesions, more recent hormone-independent models have been developed like MDA PCa 118 and Ace-1 that similarly to the PC3c model do not express AR and induce mixed lesions. Nevertheless, osteogenesis that was induced by FGF-9 in the MDA PCa 118 model was not implicated in the osteoblastic response induced by PC3c as FGF-9 expression was not statistically significantly modulated between PC3 and PC3c cells. Interestingly, when compared with PC3, PC3c cells highly expressed ET-1, a mitogenic factor for OB. ET-1 is known to contribute to osteoblastic progression of prostate cancer cells by stimulating OB proliferation through the negative regulation of the inhibitor of the Wnt signaling, DKK1 which may explain, at least in part, the decrease of 
DKK1 observed in PC3c cells. Moreover, a decrease of DKK1 serum level in patients with advanced prostate cancer has been reported to be associated with occurrence of osteoblastic lesions which suggests that DKK1 inhibition in PC3c cells may contribute to the osteoblastic phenotype induced by these cells. BMPs have also been implicated in the formation of new bone induced by prostate cancer and the inhibition of BMPs by their inhibitor Noggin in C4-2B cells induces a decrease in the osteoblastic response, suggesting that the low expression level of Noggin in PC3c cells compared with PC3 cells may also contribute to the osteoblastic lesions induced by PC3c cells. Finally the over-expression of OPG may also contribute to the osteoblastic response induced by PC3c cells by limiting 9 New Androgen-Resistant Bone Metastasis Model OC differentiation. Based on OC and OB in vitro assay and TRAP staining in vivo, it appears that PC3c cells can also over stimulate osteoclastogenesis directly by acting on OC precursors and indirectly by increasing the RANKL/OPG ratio by OBs conducting to a general bone remodeling stimulation. On the other side, the RANKL/OPG ratio was not modulated by osteocytes like MLO-Y4 cells. Concerning osteocyte involvement into prostate cancer progression in bone, we found that the expression of SOST, an inhibitor of Wnt signaling, was induced by PC3 cells conditioned medium, suggesting a direct effect of osteocytes on OB differentiation during tumor bone progression. Meanwhile the exp