514 ing include inhibitory Smads (I-Smads/Smad6 and 7), Ski/SnoN, and Smurfs (Smad ubiquitination regulatory factors) [44,45]. I-Smads compete with R-Smads for the ac- tivated type I receptor and act as antagonists of R-Smad and Co-Smad signaling [46]. Between the two known I-Smads, Smad6 preferentially inhibits BMP signaling pathways, whereas Smad7 blocks TGF-β superfamily sig- naling pathways [46]. Mechanistically, I-Smads stably in- teract with the activated type I receptors, whereas R- Smads rapidly dissociate from these receptors. In addition, I-Smads, especially Smad6, compete with Co-Smad for the activated R-Smads. The physical interaction between R-Smads and Co-Smad is also regulated by Ski/SnoN; these proteins interfere with the process of complex for- mation between activated R-Smads and Co-Smad [47]. The last known endogenous mechanism of inhibiting BMP sig- naling involves the ubiquination-induced degradation via Smurfs [45]. UROLOGIC IMPLICATIONS OF BMP SIGNALING In the context of the genitourinary system, BMPs are im- portant for normal renal development. Although many BMPs are expressed during the organogenesis of the meta- nephric kidney [48], BMP-7 is expressed in both the ure- teric epithelium and the mesenchyme throughout embry- onic development [49]. BMP-7 knockout mice have bi- lateral renal agenesis, suggesting that BMP-7 is absolutely required for the proper formation of the kidneys [50]. On the other hand, the exact function of BMPs in the adult kid- ney is still largely unknown. Recently, Mitu and Hirsch- berg suggested a strong association between BMPs and chronic renal disease such as diabetic nephropathy [51]. While BMP-7 is heavily expressed by the podocytes, distal tubules, and collecting ducts in the adult kidney, ex- pression of BMP-7 disappears in early fibrogenic renal diseases. Interestingly, the exogenous administration or transgenic overexpression of BMP-7 reduces renal fibro- genesis and better preserves nephron function and struc- tural integrity [51]. 　In addition to the development of the genitourinary tract, BMPs have also been implicated in the cellular growth and progression of malignancy. In an effort to eluci- date the molecular mechanisms of renal cell carcino- genesis, Kim et al investigated the potential role of BMP-6 and its receptors in renal cell carcinoma (RCC) cells [52]. They demonstrated that human RCC tissues frequently had decreased levels of expression of BMP receptor type II (BMP-RII), which was associated with insensitivity to the growth-inhibitory effect of BMP-6 in human RCC cells. These observations suggest that BMP-6 is a potent in- hibitor of growth in human RCC cells and that abnormal expression of BMP-RII results in a resistance to the growth-inhibitory effect of BMP-6. Similarly, Basic-Jukic et al demonstrated higher BMP-6 mRNA expression levels in clear cell RCC tissue than in benign renal tissue [53]. In a more recent report, Blish et al reported that the BMP an- Korean J Urol 2010;51:511-517 Jeong et al tagonist sclerostin domain-containing 1 (SOSTDC1) was down-regulated in clear cell RCC compared with normal kidney tissue [54]. In tissue culture, SOSTDC1 suppressed BMP-7-induced phosphorylation of Smad1, -5, and -8 and Wnt-3a signaling. These observations suggest that the re- storation of SOSTDC1 expression may represent a novel therapeutic strategy for clear cell RCC because SOSTDC1 suppresses the proliferation of renal cell carcinoma cells. 　Similar to the RCC studies, Kim et al evaluated the po- tential role of BMP receptors in bladder transitional cell carcinoma (TCC) cells and demonstrated that there was a significant association between the loss of BMP-RII ex- pression and tumor grade [55]. Subsequently, they ob- served a decreased level of BMP-RII expression in a blad- der TCC cell line, TSU-Pr1, and an enhanced resistance of the growth-inhibitory effect of BMP-6. These results sug- gest that the overexpression of BMP-RII may restore BMP signaling and decrease tumor growth in bladder TCC cells. 　Compared to RCC and bladder TCC, the role of BMPs in prostate carcinogenesis has been extensively investigated during the last two decades. BMPs were initially im- plicated in the pathogenesis of osteoblastic metastasis-as- sociated prostate adenocarcinoma, because BMP-7 was frequently overexpressed in the prostate and in metastatic bone lesions [56-58]. The precise role of BMP signaling in prostate cancer, though, has been controversial. Yuen et al reported that increased expression of BMP-6 and de- creased expression of its inhibitors (noggin and sclerostin) promoted the metastatic progression of prostate cancer [59]. On the other hand, the expression of BMP-7 tended to be lower during the development and progression of pros- tate cancer, whereas its expression was highest in normal prostate glandular tissue [60]. Similarly, Buijs et al re- ported that BMP-7 can counteract the epithelial-to-mesen- chymal transition process, suggesting that BMP-7 may be a potent inhibitor of prostate cancer bone metastasis in vivo [61]. With regard to the role of BMP membrane receptors (BMPRs) in prostate cancer, Kim et al observed that the loss of expression of BMPRs occurred more frequently in high-grade prostate cancer [62]. These observations, taken together, suggest that the loss of BMPRs contribute to pros- tate cancer progression and metastasis by releasing the transformed cells from the growth-inhibitory effect of BMPs. BLOCKING BMP SIGNALING Because overactive BMP signaling is often associated with various pathologic conditions, blocking BMPs may be an effective therapeutic approach. To this end, macromole- cules such as neutralizing antibodies are currently being developed. These neutralizing antibodies contain a portion of the extracellular soluble receptors and recognize various BMP ligands as antigenic motifs and prevent the trans- duction of BMP signaling by neutralizing their activities through the antigen-antibody reaction [63]. 　Recently, Souza et al reported that the blockade of myo-