Negative Regulator Of Wnt Pathway Research Articles

Predictive impact of RNF43 mutation (mut) in patients (pts) with pMMR/MSS BRAF V600E mutated metastatic colorectal cancer (mCRC) treated with target therapy (TT) or chemotherapy (CT).

3569 Background: Encorafenib plus cetuximab is a standard option in the treatment of BRAF V600E mut mCRC pts pre-treated with at least one systemic therapy. RNF43 is a negative regulator of WNT pathway. A recent study showed that RNF43 mutation is associated with better outcome among pMMR/MSS BRAF V600E mut mCRC patients treated with TT but not in an independent cohort of pts not treated with TT (Elez et al. Nat Med 2022). However, no comparison is available between TT vs CT as second-line (2L) treatment for pMMR/MSS BRAF V600E mut mCRC according to RNF43 mutational status. Methods: The predictive impact of RNF43 mut was evaluated in a real-life dataset of 126 pMMR/MSS BRAF V600E mut mCRC pts treated with TT (consisting of BRAF inhibitor + anti-EGFR antibody ± MEK inhibitor) vs CT ± target agent as 2L treatment. A cohort of 36 pts receiving TT after 2L was also analyzed. Results: Thirty-one (25%) and 95 (75%) out of 126 pMMR/MSS BRAF V600E mut tumours were RNF43 mut and RNF43 wt, respectively. In the RNF43 mut group 14 (45%) received CT and 17 (55%) TT; in the RNF43 wt group, 56 (59%) and 39 (42%) received CT and TT, respectively. Among RNF43 mut pts, those treated with TT reported longer PFS (7.1 vs 3.0 months, HR: 0.35 95%CI: 0.16-0.76, p = 0.006) and higher ORR (42% vs 0%, p = 0.009) than those receiving CT. On the other hand, no significant difference was observed among RNF43 wt patients in terms of PFS (4.3 vs 3.7 months, HR: 0.69 95% CI: 0.45-1.05, p = 0.080) and ORR (28% vs 16%, p = 0.24). However, no significant interaction between treatment effect and RNF43 mutational status was reported in terms of PFS (pinteraction= 0.17) and ORR (pinteraction= 0.96). After excluding 36 pts in the CT group that received TT after 2L, no interaction effect was observed also in terms of OS (pinteraction= 0.53). However, among RNF43 mut pts, those treated with TT reported longer OS (16.5 vs 10.1 months; HR: 0.34 95% CI: 0.11-1.00, p = 0.049), while no significant difference was observed among RNF43 wt pts (10.6 vs 6.6 months; HR: 0.66 95% CI: 0.39-1.11; p = 0.12). In the group receiving TT after 2L, 9 (25%) out of 36 cases were RNF43 mut and achieved higher ORR (78% vs 26%, p = 0.014) and longer PFS (10.1 vs 4 months; HR: 0.35 95%CI: 0.14-0.88; p = 0.020) and OS (11.7 vs 7 months; HR: 0.35 95%CI: 0.15-0.82; p = 0.012) than RNF43 wt (N = 27). Conclusions: pMMR/MSS BRAF V600E mut mCRC patients achieve benefit from TT vs CT independently of RNF43 mutational status, but a higher magnitude of benefit from TT is observed among those with RNF43 mut tumors. These findings deserve confirmation in past and current randomized trials (i.e. BEACON and BREAKWATER).

Abstract LB-386: MicroRNA-164a activates the Wnt pathway to promote breast cancer metastasis

Abstract Breast cancer is the most common type of malignant tumor among women, and is the second leading cause of cancer-related death in women. The triple negative breast cancer (TNBC) remains is one of the major contributors of breast cancer mortality. TNBCs are a type of aggressive breast cancer that exhibits a high rate of distant metastasis and poor survival compared with other breast cancer subtypes. Although immunotherapy with PD-1 and PD-L1 blockade have achieved durable responses in a number of tumors, including TNBC. However, the overall response rates were low. Thus, elucidating the mechanisms responsible for tumor metastasis and the interaction of tumor cells with their microenvironments is critical for developing effective therapeutic approaches to treat metastatic breast cancer. Our results suggest that miR-146 can induce oncogenic transformation and tumor metastasis in the context of breast cancer. We found that miR-146a is highly expressed in TNBC cells, and is critical for the expansion of tumor-initiating cells in breast cancer growth and metastasis. Our preliminary data further indicate that miR-146a promotes breast tumorigenesis by targeting negative regulators of Wnt pathway, which is frequently altered in various tumors. The goal of this study to develop novel therapeutic approaches that could ultimately lead to effective treatment for breast cancer, particularly TNBC. Citation Format: Melvin Kantono, Wei Sun, Beichu Guo. MicroRNA-164a activates the Wnt pathway to promote breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-386.

The lncRNA H19 positively affects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter.

The still largely obscure molecular events in the glioblastoma oncogenesis, a primary brain tumor characterized by an inevitably dismal prognosis, impel for investigation. The importance of Long noncoding RNAs as regulators of gene expression has recently become evident. Among them, H19 has a recognized oncogenic role in several types of human tumors and was shown to correlate to some oncogenic aspects of glioblastoma cells. Here we, hypothesyze that in glioblastoma H19 exerts its function through the interaction with the catalytic subunit of the PRC2 complex, EZH2. By employing a factor analysis on a SAGE dataset of 12 glioblastoma samples, we show that H19 expression in glioblastoma tissues correlates with that of several genes involved in glioblastoma growth and progression. H19 knock-down reduces viability, migration and invasiveness of two distinct human glioblastoma cell lines. Most importantly, we provide a mechanistic perspective about the role of H19 in glioblastoma cells, by showing that its expression is inversely linked to that of NKD1, a negative regulator of Wnt pathway, suggesting that H19 might regulate NKD1 transcription via EZH2-induced H3K27 trimethylation of its promoter. Indeed, we showed that H19 binds EZH2 in glioblastoma cells, and that EZH2 binding to NKD1 and other promoters is impaired by H19 silencing.In this work we describe H19 as part of an epigenetic modulation program executed by EZH2, that results in the repression of Nkd1. We believe that our results can provide a new piece to the complex puzzle of H19 function in glioblastoma.

MiR-4326 promotes lung cancer cell proliferation through targeting tumor suppressor APC2

microRNAs have been reported to play vital role in lung cancer proliferation and metastasis; the role of miR-4326 in tumor progression has not been studied. Here, we studied the effect of miR-4326 on lung cancer cell proliferation; we found that miR-4326 was significantly upregulated in lung cancer tissues determined using TCGA dataset and clinical specimens, meanwhile it was also upregulated in lung cancer cells. Overexpression of miR-4326 promoted lung cancer cell proliferation analyzed by MTT, soft agar growth, and BrdU incorporation assay, while miR-4326 knockdown suppressed lung cancer cell proliferation. We found miR-4326 targets tumor suppressor adenomatous polyposis coli 2 (APC2), which is a negative regulator of Wnt pathway, by binding to the 3'UTR of APC2. Wnt pathway could increase Cyclin D1 and c-MYC expression, we also found that miR-4326 could increase their expression, suggesting that APC2 was the target of miR-4326. Moreover, double knockdown of APC2 and miR-4326 promoted lung cancer cell proliferation, confirming that miR-4326 promoted lung cancer cell proliferation by inhibiting APC2.

Genome-wide analysis of metastases to reveal association of pathway activation with abiraterone acetate/prednisone (AA/P) primary resistance and cell cycle proliferation pathway activation with response duration in metastatic castrate resistant prostate cancer (mCRPC).

5053 Background: Genomic aberrations associated with resistance/response to AA/P are not known. In a prospective study we assessed whole-exome/RNA-seq based aberrations in CRPC metastatic biopsies for identifying molecular markers associated with primary resistance and response duration. Methods: Sequencing of metastatic biopsies was performed for analyzing molecular aberrations that predict primary resistance (defined as progression at 12-weeks of therapy (non-responders) using PSA, RECIST, bone scan criteria per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders and in genes differentially expressed between non-responders and responders using a “risk ratio” (RR) of ≥2. Cox regression models with multiple gene network pathways were used for determining association with time to treatment change (TTTC). Results: Of 92 enrolled pts 82 had complete whole-exome, RNA-seq & 12-week outcome data available for analysis. At 12-weeks 33/82 had progressed. Using a RR of ≥2, 113 genes were more frequently mutated in non-responders & 292 in responders. In non-responders, gene network analysis revealed frequent mutations in Wnt/β-catenin pathway genes; frequent deletion of negative regulators of Wnt pathway ( DKK4, SFRP2, LRP6). Gene expression analyses revealed significantly reduced expression levels of Wnt/β-catenin pathway inhibitors and increased expression levels of cell cycle proliferation (CCP) genes in non-responders. Median study follow up was 32 months during which time 58/82 pts progressed and switched treatments. Median TTTC was 10.1 months (IQR:4.4-24.1). In multivariate analysis CCP scores of ≥50 predicted shorter TTTC (HR = 2.11, 95% CI: 1.17-3.80; p = 0.01). Conclusions: In metastases Wnt/β-catenin pathway activation is associated with primary AA/P resistance and increased CCP with acquired drug resistance. These findings offer molecular based predictive biomarkers in CRPC stage treatment. Clinical trial information: NCT#01953640.

Association of Wnt pathway activation with prechemotherapy abiraterone acetate resistance in metastatic castration-resistant prostate cancer (mCRPC) by genome-wide analysis of metastases.

175 Background: Genome and transcriptome aberrations associated with primary resistance to abiraterone acetate/prednisone (AA/P) in mCRPC are not known. In a prospective trial (NCT#01953640) we assessed whole-exome and RNA-seq based aberrations in metastases of CRPC stage patients (pts) for identifying markers associated with primary resistance to AA/P. Methods: Whole-exome and RNA-seq of biopsies from metastases was performed followed by analyses for association between genomic aberrations & primary resistance. Primary resistance was defined by progression on AA/P after 12-weeks of therapy(non-responders) using PSA, RECIST, bone scan and symptom criteria (per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders, and also in genes that were differentially expressed between non-responders and responders and a “risk ratio” (RR) was calculated thereof. Results: Between 6/2013 & 8/2015, 92 pts were enrolled of which 82 had complete whole-exome, RNA-seq and 12-week outcome data available for analysis. Median age was 72.5 yrs (IQR: 68.5-78); median PSA-18 ng/ml (IQR: 8.1- 46.6). At 12-weeks 33/82 had progressed. Using the RR of 2 as threshold, we identified 113 and 292 genes that were more frequently mutated in non-responders & responders respectively. Among the 113 genes, OBSCN, ADAM21, LPHN3, DOCK10 ( P = 0.08, RR= inf) & USP42 ( P = 0.16, RR = 5.71) were the top candidates.Gene network analysis revealed that in non-responders, genes involved in the Wnt/β-catenin pathway were frequently mutated and negative regulators of Wnt pathway ( DKK4, SFRP2 & LRP6) were also frequently deleted. Gene expression analyses revealed the expression levels of Wnt/β-catenin pathway inhibitors were significantly reduced while expression levels of cell cycle regulatory genes were significantly increased in non-responders. Conclusions: In this study we observed Wnt/β-catenin pathway activation to be associated with primary AA/P resistance. This finding offers a potential for the development of predictive biomarkers and modulation of targeted pathways to overcome AA/P resistance. Clinical trial information: NCT# 01953640.

Carbonic Anhydrase IV Inhibits Colon Cancer Development by Inhibiting WNT Signaling Pathway Through Targeting WTAP-WT1-TBL1 Axis

Using Methylated DNA Immunoprecipitation (MeDIP) combined with microarray assay, Carbonic Anhydrase IV (CA4) was identified to be preferentially methylated in colorectal cancer (CRC). CA4 is a member of carbonic anhydrases family which catalyzes the reversible hydration of carbondioxide. However, the functional role of CA4 in CRC is still unclear. CA4 promoter methylation status was evaluated by bisulfite genomic sequencing. The biological functions of CA4 were determined in vitro cell viability, colony formation, cell apoptosis, and cell cycle assays and in vivo tumorigenicity assay. The cooperators of CA4 were identified by co-immunoprecipitation assay, mass spectrometry, promoter luciferase reporter assay, chromatin immunoprecipitation assay and gel shift assay. Clinical application of CA4 methylation was assessed in 115 primary CRC tissues. We first screened the expression status of CA4 in 9 CRC cell lines and primary CRC tissues. CA4 was silenced in all 9 cell lines and the mean protein expression level of CA4 was significantly lower in CRC tissues as compared to their adjacent normal tissues (P<0.01). Silence of CA4 was mediated by promoter methylation. Methylation status of CA4 was detected in 75.7% (87/115) of CRC patients. Multivariate analysis and recurrence curve revealed that patients with CA4 methylation had significantly higher opportunities to suffer from cancer recurrence (P < .05). Re-expression of CA4 in CRC cell lines suppressed cell viability (P < .001) and colony formation (P < .01), and caused cell cycle arrest in G1 phase (P < .05). CA4 also induced cell apoptosis (P < .01), concomitant with enhanced protein expression of pro-apoptotic factors cleaved caspase3, caspase7, caspase8 and PARP. The in vivo growth of CRC cells in nude mice was also markedly inhibited by stable transfection with vector harboring CA4 (P < .05). We further tested the molecular mechanisms of CA4 in CRC as a tumor suppressor. Co-immunoprecipitation assay revealed that Wilms tumor 1-associating protein (WTAP) is directly interacted with CA4. Transfection of CA4 in CRC cell lines induced WTAP protein degradation through poly-ubiquitination. Moreover, CA4 promoted transcriptional activity of Wilms tumor 1 (WT1), a negative regulator of Wnt pathway, leading to induction of transducing β-like protein 1(TBL1). TBL1 induced β-catenin degradation through a non-phosphorylated way which finally inhibit Wnt signaling pathway activity. Epigenetic inactivation of CA4 is a common event in CRC which may play a pivotal role as a novel tumor suppressor in CRC carcinogenesis. CA4 inhibit Wnt signaling pathway by targeting WTAP-WT1-TBL1 axis. Detection of CA4 methylation may serve as an independent biomarker for the recurrence of CRC.

Structure-based design of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors to activate Wnt/β-catenin pathway

Deregulation of Wnt/β-catenin pathway is closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), and glycogen synthase kinase 3β (GSK-3β), the central negative regulator of Wnt pathway, is regarded as an important target for these diseases. Here, we report a series of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors by rational-design and synthesis, which show high selectivity against GSK-3β over Cyclin-dependent kinase 2 (CDK2), and significantly activate the cellular Wnt/β-catenin pathway. The structure–activity relationship of these GSK-3β inhibitors was also explored by in silico molecular docking.

Two Fingers on the Pulse of Wnt: Molecular Mechanism of Wnt Pathway Regulation by RING‐finger E3 Ligases ZNRF3/RNF43

Wnt signaling pathways play critical roles in embryonic development and tissue homeostasis. The homologous transmembrane E3 ubiquitin ligases, ZNRF3 and RNF43, are critical negative regulators of Wnt pathway by mediating the ubiquitination and degradation of Wnt co‐receptors Frizzled (FZD) and LRP6, and this activity is counteracted by secreted Wnt agonists R‐spondin (RSPO) proteins. Despite increasing interest in these E3 ligases, the mechanism by which ZNRF3/RNF43 recognizes the Wnt receptors remains unclear. Here we identified ZRBP1 functions as an adaptor that recruits ZNRF3/RNF43 to Wnt receptors. ZRBP1 knockout phenocopies ZNRF3/RNF43 knockout, leading to increased cell surface levels of FZD and LRP6. Mechanistically, ZRBP1 is required for ZNRF3/RNF43‐mediated ubiquitination and degradation of FZD. The intracellular domain of ZNRF3/RNF43 physically interacts with ZRBP1, and this interaction is crucial for the Wnt inhibitory activity of the E3 ligases. ZRBP1 also interacts with FZD, and this binding is required for down‐regulation of FZD. Our study reveals ZRBP1 acts as a critical adaptor to recruit negative regulators ZNRF3/RNF43 to Wnt receptors to ensure proper control of pathway activity, and presents new opportunities to modulate Wnt pathway activity.

Nkd2, a negative regulator of Wnt pathway, delays mitotic exit in Hela cell

Frequent amplification and abundant expression of Nkd2 has been identified in malignant peripheral nerve sheath tumors (MPNSTs), dominant for genomic instability, who is involved in both Wnt pathway and EGFR signaling pathway. As a negative regulator of Wnt pathway, Nkd2 suppresses Wnt signaling by binding to Dvl1 and causing its ubiquitination followed by 26S proteasome degradation. On the other hand, it interacts with TGF-α for its transportation to basolateral plasma membrane in polarized epithelial cells. It is of interest to determine if Nkd2 over-expression contributes to tumorigenesis and genomic instablity. In this paper, we found that cells expressing NKD2 delayed mitotic exit stage after double thymidine block synchronization, but aneuploidy was not detected in these cells. This was further confirmed by Western blotting. In nocodazole-synchronised cells, Cyclin B1 degradation was delayed with Nkd2 over-expression compared to control group. Given many previous publications showed that Wnt pathway components are involved in mitotic progression. Further investigation on Nkd2’s function in mitosis might give more clues on MPNSTs pathological progression.

Abnormal hypermethylation and clinicopathological significance of Axin gene in lung cancer

Axin is an important negative regulator of Wnt pathway. We have reported that reduced expression of Axin could be detected in lung cancer tissues, but the mechanism is not clear. By analyzing the genomic sequence, we note that Axin gene promoter is rich in CpGs. Little is known about the methylation status of Axin gene in lung cancer. So, nested MSP and RT-PCR were used to study the methylation status and mRNA expression of Axin gene in lung cancer tissues and cell lines. The results showed that hypermethylated Axin gene promoter and reduced mRNA expression level of Axin could be detected in lung cancer tissues but not in their paired autologous normal lung tissues (P < 0.01). The hypermethylated Axin gene promoter significantly correlated with the degree of differentiation (P = 0.03), lymph node metastasis (P = 0.048) and TNM classifications (P = 0.032). Demethylation reagent 5-aza-2-deoxycytidine significantly up-regulate Axin expression in BE1 cells (with hypermethylated Axin gene promoter) but not in H460 cells (with unmethylated Axin gene promoter). MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and transwell matrigel invasion assay showed that 5-aza-2-deoxycytidine treatment inhibited cell growth and invasion more significantly in BE1 cells than that in H460 cells. Our data indicate that hypermethylated Axin gene significantly correlates with the progression of lung cancer and might serve as a new target of clinical therapy for lung cancer patients in future.

Abstract 3419: N-myc downstream regulated gene 1, NDRG1, modulates Wnt-β-catenin signaling and pleiotropically suppresses metastasis

Abstract It is of paramount interest to delineate the underlining molecular pathways of cancer metastasis in order to identify a novel therapeutic target for this devastating disease. Previously, we identified NDRG1 as a tumor metastasis suppressor gene and found that it is negatively involved in metastatic progression of prostate and breast cancer. Herein, we sought to determine how NDRG1 gene exerts its metastasis suppressor function. We used the yeast two-hybrid system to identify proteins interacting with NDRG1, and also the phospho-site profiling system to search for potential signaling pathway involved in NDRG1 function. We found that NDRG1 interacted with Wnt receptor, LRP6, and blocked its phosphorylation. Moreover, NDRG1 induced phosphorylated- activation of GSK3β (Tyr279/216), an essential negative regulator of Wnt pathway, followed by inhibition of β-catenin/TCF transcriptional activity. Further investigations revealed that NDRG1 inhibited the expression of ATF3, a potent metastasis promoter, through Wnt- β-catenin/TCF signaling. Consistently, the results of our immunohisochemical studies revealed an inverse correlation between NDRG1 expression and ATF3 and membrane β-catenin, respectively, while ATF3 expression was significantly correlated with cytoplasm/nuclear expression of β-catenin in prostate cancer patients. When we assessed the possible steps of metastasis cascade that were affected by NDRG1, we found that NDRG1 dramatically inhibited Wnt-induced EMT of tumor cells. Furthermore, NDRG1 not only significantly reduced local invasive ability of tumor cells, but also impaired the later steps of invasion-metastasis cascade including infiltration, initial survival and extravasation in the mice lung parenchyma. To determine whether NDRG1 indeed suppresses metastasis via the inhibition of Wnt pathway in vivo, we isolated tumor cells from a MMTV-Wnt1 mouse and established a series of cell lines with or without NDRG1 expression in combination with a dominant active Wnt signaling. Our results indicate that NDRG1 significantly decreased metastasis while it did not affect the primary tumor growth. However, a dominant active form of β-catenin effectively overcame the metastasis-suppressive effect of NDRG1. Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumor cells to thrive in circulation and distant organs in animal models. Finally, using a combined expression status of Wnt and NDRG1 as a signature, we could stratify patients who have significant higher relapse or metastasis incidence than others in clinical databases. Taken together, our results revealed a novel mechanism of metastasis suppression by which NDRG1 suppresses pleiotropic effects of Wnt signaling on metastatic cascade through impeding the upstream activation of Wnt co-receptor LRP6. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3419. doi:1538-7445.AM2012-3419

Essential Role of Nuclear Factor of Activated T Cells (NFAT)-mediated Wnt Signaling in Osteoblast Differentiation Induced by Strontium Ranelate

The antiosteoporotic treatment strontium ranelate (SrRan) was shown to increase bone mass and strength by dissociating bone resorption and bone formation. To identify the molecular mechanisms of action of SrRan on osteoblasts, we investigated its effects on calcineurin-NFAT (nuclear factor of activated T cells) signaling, an important calcium sensitive pathway controlling bone formation. Using murine MC3T3-E1 and primary murine osteoblasts, we demonstrate that SrRan induces NFATc1 nuclear translocation, as shown by immunocytochemical and Western blot analyses. Molecular analysis showed that SrRan increased NFATc1 transactivation in osteoblasts, an effect that was fully abrogated by the calcineurin inhibitors cyclosporin A or FK506, confirming that SrRan activates NFATc1 signaling in osteoblasts. This has functional implications because calcineurin inhibitors blunted the enhanced osteoblast replication and expression of the osteoblast phenotypic markers Runx2, alkaline phosphatase, and type I collagen induced by SrRan. We further found that SrRan increased the expression of Wnt3a and Wnt5a as well as beta-catenin transcriptional activity in osteoblasts, and these effects were abolished by calcineurin inhibitors. The Wnt inhibitors sFRP1 and DKK1 abolished SrRan-induced osteoblast gene expression. Furthermore, blunting the Wnt5a receptor Ryk or RhoA that acts downstream of Ryk abrogated cell proliferation and osteoblast gene expression induced by SrRan. These results indicate that activation of NFATc1 and downstream canonical and non-canonical Wnt signaling pathways mediate SrRan-induced osteoblastic cell replication and differentiation, which provides novel insights into the mechanisms of action of this antiosteoporotic agent in osteoblastogenesis.

Targeting the Wnt signaling pathway to augment bone formation

Recent discoveries in humans and mice have revealed that the Wnt (Wingless and Int-1) signaling pathway is responsible for a complex array of functions in maintaining bone homeostasis. The Wnt proteins are key modulators of mesenchymal lineage specification and regulate most aspects of osteoblast physiology and postnatal bone acquisition by controlling the differentiation and activity of osteoblasts and osteoclasts. Initial reports have indicated that activators of Wnt signaling are potent promoters of osteogenesis; however, systemic hyperactivation of the canonical Wnt pathway could potentially accelerate neoplastic transformation and subsequent tumor growth. Alternatively, recent investigations of natural soluble antagonists of Wnt signaling in bone suggest the possibilities of bone-specific therapies targeting the negative regulators of Wnt pathway, especially sclerostin. With this new knowledge, novel pharmacologic interventions that alter Wnt signaling are being evaluated for the management of osteoporosis. In this article, we briefly describe the Wnt signaling elements, their characterized role in bone, and summarize the current knowledge on the potential to enhance bone formation through the manipulation of Wnt signaling antagonists.