Kegg Pathway: Wnt signaling pathway

Am J Pathol. 2009 Nov 5;
Chen Y, Hu Y, Zhou T, Zhou KK, Mott R, Wu M, Boulton M, Lyons TJ, Gao G, Ma JX

Although Wnt signaling is known to mediate multiple biological and pathological processes, its association with diabetic retinopathy (DR) has not been established. Here we show that retinal levels and nuclear translocation of beta-catenin, a key effector in the canonical Wnt pathway, were increased in humans with DR and in three DR models. Retinal levels of low-density lipoprotein receptor-related proteins 5 and 6, coreceptors of Wnts, were also elevated in the DR models. The high glucose-induced activation of beta-catenin was attenuated by aminoguanidine, suggesting that oxidative stress is a direct cause for the Wnt pathway activation in diabetes. Indeed, Dickkopf homolog 1, a specific inhibitor of the Wnt pathway, ameliorated retinal inflammation, vascular leakage, and retinal neovascularization in the DR models. Dickkopf homolog 1 also blocked the generation of reactive oxygen species induced by high glucose, suggesting that Wnt signaling contributes to the oxidative stress in diabetes. These observations indicate that the Wnt pathway plays a pathogenic role in DR and represents a novel therapeutic target.

Mol Syst Biol. 2009; 5: 315
Miller BW, Lau G, Grouios C, Mollica E, Barrios-Rodiles M, Liu Y, Datti A, Morris Q, Wrana JL, Attisano L

Large-scale proteomic approaches have been used to study signaling pathways. However, identification of biologically relevant hits from a single screen remains challenging due to limitations inherent in each individual approach. To overcome these limitations, we implemented an integrated, multi-dimensional approach and used it to identify Wnt pathway modulators. The LUMIER protein-protein interaction mapping method was used in conjunction with two functional screens that examined the effect of overexpression and siRNA-mediated gene knockdown on Wnt signaling. Meta-analysis of the three data sets yielded a combined pathway score (CPS) for each tested component, a value reflecting the likelihood that an individual protein is a Wnt pathway regulator. We characterized the role of two proteins with high CPSs, Ube2m and Nkd1. We show that Ube2m interacts with and modulates beta-catenin stability, and that the antagonistic effect of Nkd1 on Wnt signaling requires interaction with Axin, itself a negative pathway regulator. Thus, integrated physical and functional mapping in mammalian cells can identify signaling components with high confidence and provides unanticipated insights into pathway regulators.

Cancer Res. 2009 Nov 3;
Noubissi FK, Goswami S, Sanek NA, Kawakami K, Minamoto T, Moser A, Grinblat Y, Spiegelman VS

Wnt and Hedgehog signaling pathways play central roles in embryogenesis, stem cell maintenance, and tumorigenesis. However, the mechanisms by which these two pathways interact are not well understood. Here, we identified a novel mechanism by which Wnt signaling pathway stimulates the transcriptional output of Hedgehog signaling. Wnt/beta-catenin signaling induces expression of an RNA-binding protein, CRD-BP, which in turn binds and stabilizes GLI1 mRNA, causing an elevation of GLI1 expression and transcriptional activity. The newly described mode of regulation of GLI1 seems to be important to several functions of Wnt, including survival and proliferation of colorectal cancer cells. [Cancer Res 2009;69(22):8572-8].

Endocrinology. 2009 Nov 3;
Sonderegger S, Haslinger P, Sabri A, Leisser C, Otten JV, Fiala C, Knöfler M

Invasion of human trophoblasts is promoted through activation of wingless (Wnt) signaling, suggesting a role of the pathway in placental development and morphogenesis. However, details on the process such as involvement of canonical and/or noncanonical Wnt signaling cascades as well as their target genes are largely unknown. Hence, signal transduction via canonical Wnt signaling or phosphatidylinositide 3-kinase (PI3K)/AKT and their cross talk as well as trophoblast-specific protease expression were investigated in trophoblastic SGHPL-5 cells and primary extravillous trophoblasts purified from first-trimester placentas. Western blot analyses revealed that the recombinant Wnt ligand Wnt-3A increased phosphorylation of AKT and the downstream kinase glycogen synthase kinase (GSK)-3beta as well as accumulation of activated, nuclear beta-catenin. In accordance, luciferase expression of a canonical Wnt/TCF reporter and cell migration in first-trimester villous explant cultures and of SGHPL-5 cells were stimulated. Chemical inhibition of PI3K abolished Wnt-dependent phosphorylation of AKT and GSK-3beta and trophoblast motility but did not affect appearance of activated beta-catenin or Wnt/TCF reporter activity. In contrast, inhibition of the canonical pathway through soluble Dickkopf-1 did not influence AKT and GSK-3beta phosphorylation but reduced Wnt reporter activity, accumulation of active beta-catenin, and cell migration. Both inhibitors decreased Wnt-3A-induced secretion of pro- and active matrix metalloproteinase-2 from SGHPL-5 cells and pure EVT. The data suggest that Wnt-3A may activate canonical Wnt signaling and PI3K/AKT through distinct receptors. The two signaling cascades act independently in trophoblasts; however, both pathways promote Wnt-dependent migration and the release of matrix metalloproteinase-2, which has been identified as novel Wnt target in invasive trophoblasts.

Neural Dev. 2009 Nov 2; 4(1): 41
Varela-Nallar L, Grabowski CP, Alfaro IE, Alvarez AR, Inestrosa NC

ABSTRACT: BACKGROUND: The Wnt signaling pathway regulates several fundamental developmental processes and recently has been shown to be involved in different aspects of synaptic differentiation and plasticity. Some Wnt signaling components are localized at central synapses, and it is thus possible that this pathway could be activated at the synapse. RESULTS: We examined the distribution of the Wnt receptor Frizzled-1 in cultured hippocampal neurons and determined that this receptor is located at synaptic contacts co-localizing with presynaptic proteins. Frizzled-1 was found in functional synapses detected with FM1-43 staining and in synaptic terminals from adult rat brain. Interestingly, overexpression of Frizzled-1 increased the number of clusters of Bassoon, a component of the active zone, while treatment with the extracellular cysteine-rich domain (CRD) of Frizzled-1 decreased Bassoon clustering, suggesting a role for this receptor in presynaptic differentiation. Consistent with this, treatment with the Frizzled-1 ligand Wnt-3a induced presynaptic protein clustering and increased functional presynaptic recycling sites, and these effects were prevented by co-treatment with the CRD of Frizzled-1. Moreover, in synaptically mature neurons Wnt-3a was able to modulate the kinetics of neurotransmitter release. CONCLUSIONS: Our results indicate that the activation of the Wnt pathway through Frizzled-1 occurs at the presynaptic level, and suggest that the synaptic effects of the Wnt signaling pathway could be modulated by local activation through synaptic Frizzled receptors.

Oncogene. 2009 Nov 2;
Zhang J, Li Y, Liu Q, Lu W, Bu G

Although Wnt signaling activation is frequently observed in human breast cancer, mutations in genes encoding intracellular components of the Wnt signaling pathway are rare. We found that the expression of Wnt signaling co-receptor, LRP6, is upregulated in a subset of human breast cancer tissues and cell lines. To examine whether the overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of beta-catenin from membrane to cytoplasmic/nuclear fractions. The expression of several Wnt target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared with wild-type littermate controls. Several matrix metalloproteinases are upregulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell-surface receptor level can contribute to breast cancer tumorigenesis.Oncogene advance online publication, 2 November 2009; doi:10.1038/onc.2009.339.

Aging Cell. 2009 Oct 30;
Cao JN, Gollapudi S, Sharman EH, Jia Z, Gupta S

Summary: Aging is associated with progressive T cell deficiency and increased incidence of infections, cancer, and autoimmunity. In this perhaps most comprehensive study, we have compared the gene expression profiles in CD8+ T cells from aged and young healthy subjects using Affymetrix microarray Human Genome U 133A-2 GeneChips. A total of 5.2% (754) of the genes analysed had known functions and displayed statistically significant age-associated expression changes. These genes were involved in a broad array of complex biological processes, mainly in nucleic acid and protein metabolism. Functional groups, in which down-regulated genes were overrepresented, were the following: RNA transcription regulation, RNA and DNA metabolism, intracellular (Golgi, endoplasmic reticulum (ER) and nuclear) transportation, signaling transduction pathways (T cell receptor, Ras/MAPK, JNK/Stat, PI3/AKT, Wnt, TGFbeta, IGF and insulin), and the ubiquitin cycle. In contrast, the following functional groups contained more up-regulated genes than expected: response to oxidative stress and cytokines, apoptosis, and the MAPKK signaling cascade. These age-associated gene expression changes may be responsible for impaired DNA replication, RNA transcription, and signal transduction, possibly resulting in instability of cellular and genomic integrity, and alterations of growth, differentiation, apoptosis and anergy in human aged CD8+ T cells.

Invest Ophthalmol Vis Sci. 2009 Oct 29;
Zhou T, Hu Y, Chen Y, Zhou K, Zhang B, Gao G, Ma JX

PURPOSE. Our previous studies showed that the Wnt signaling pathway is activated in the retina and retinal pigment epithelium of animal models of age-related macular degeneration (AMD) and diabetic retinopathy (DR). The purpose of this study is to investigate the role of the canonical Wnt pathway in pathogenesis of these diseases. METHODS. The Wnt pathway was activated using the Wnt3a conditioned medium and adenovirus expressing a constitutively active mutant of beta-catenin (Ad-S37A) in ARPE19, a cell line derived from human RPE. Ad-S37A was injected into the vitreous of normal rats to activate the Wnt pathway in the retina. Accumulation of beta-catenin was determined by Western blot analysis, and its nuclear translocation revealed by immunocytochemistry. Inflammatory factors were quantified by Western blot analysis and ELISA. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS) generation, and nitrotyrosine levels. RESULTS. The Wnt3a conditioned medium and Ad-S37A both increased beta-catenin levels and its nuclear translocation in ARPE19 cells, suggesting activation of the canonical Wnt pathway. The activation of the Wnt pathway significantly up-regulated expression of VEGF, NF-kappaB and TNF-alpha. Further, Ad-S37A induced ROS generation in a dose-dependent manner. Wnt3a also induced a 2-fold increase of ROS generation. Intravitreal injection of Ad-S37A up-regulated expression of VEGF, ICAM-1, NF-kappaB, TNF-alpha and increased protein nitrotyrosine levels in the retina of normal rats. CONCLUSION. Activation of the canonical Wnt pathway is sufficient to induce retinal inflammation and oxidative stress and plays a pathogenic role in AMD and DR.

Trends Endocrinol Metab. 2009 Oct 27;
Boyer A, Goff AK, Boerboom D

The WntS are an expansive family of glycoprotein signaling molecules known mostly for the roles they play in embryonic development. Wnt signaling first caught the attention of ovarian biologists when it was reported that the inactivation of Wnt4 in mice results in partial female-to-male sex reversal and oocyte depletion. More recently, studies using loss- and gain-of-function transgenic mouse models demonstrated the requirement for Wnt4, Fzd4 and Ctnnb1, components of the Wnt pathway, for normal folliculogenesis, luteogenesis and steroidogenesis, and showed that dysregulated Wnt signaling can cause granulosa cell tumor development. This review covers our current knowledge of Wnt signaling in ovarian follicles, highlighting both the great promise and the many unresolved questions of this emerging field of research.

J Bone Miner Res. 2009 Oct 29;
Kamiya N, Kobayashi T, Mochida Y, Yu PB, Yamauchi M, Kronenberg HM, Mishina Y

Abstract The BMP and Wnt signaling pathways both contribute essential roles in regulating bone mass. However, the molecular interactions between these pathways in osteoblasts are poorly understood. We recently reported that osteoblast-targeted conditional knockout (cKO) of BMP receptor type IA (BMPRIA) resulted in increased bone mass during embryonic development, where diminished expression of Sost as a downstream effector of BMPRIA resulted in increased Wnt/beta-catenin signaling. Here, we report that Bmpr1a cKO mice exhibit increased bone mass during weanling stages, again with evidence of enhanced Wnt/beta-catenin signaling as assessed by Wnt reporter TOPGAL mice and TOPFLASH-luciferase. Consistent with negative regulation of the Wnt pathway by BMPRIA signaling, treatment of osteoblasts with dorsomorphin, an inhibitor of Smad-dependent BMP signaling, enhanced Wnt signaling. In addition to Sost, Wnt inhibitor Dkk1 was also downregulated in cKO bone. Expression levels of Dkk1 and Sost were upregulated by BMP2 treatment and downregulated by Noggin. Moreover, expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype. These effectors are differentially regulated by MAPK p38, as pre-treatment of osteoblasts with SB202190 blocked BMP2-induced Dkk1 expression but not Sost. These results demonstrate that BMPRIA in osteoblasts negatively regulates endogenous bone mass and Wnt/beta-catenin signaling, and that this regulation may be mediated by the activities of Sost and Dkk1. This study highlights several interactions between BMP and Wnt signaling cascades in osteoblasts that may be amenable to therapeutic intervention for the modification of bone mass density.

J Biol Chem. 2009 Oct 28;
Shi F, Cheng Y, Wang XL, Edge AS

Atoh1, a basic helix-loop-helix transcription factor, plays a critical role in the differentiation of several epithelial and neural cell types. We found that beta-catenin, the key mediator of the canonical Wnt pathway, increased expression of Atoh1 in mouse neuroblastoma cells and neural progenitor cells, and baseline Atoh1 expression was decreased by siRNA directed at beta-catenin. The upregulation of Atoh1 was caused by an interaction of beta-catenin with the Atoh1 enhancer that could be demonstrated by chromatin immunoprecipitation. We found that two putative Tcf-Lef sites in the 3'enhancer of the Atoh1 gene displayed an affinity for beta-catenin and were critical for the activation of Atoh1 transcription since mutation of either site decreased expression of a reporter gene downstream of the enhancer. Tcf-Lef co-activators were found in the complex that bound to these sites in the DNA together with beta-catenin. Inhibition of Notch signaling, which has previously been shown to induce bHLH transcription factor expression, increased beta-catenin expression in progenitor cells of the nervous system. Since this could be a mechanism for upregulation of Atoh1 after inhibition of Notch, we tested whether siRNA to beta-catenin prevented the increase in Atoh1 and found that beta-catenin expression was required for increased expression of Atoh1 after Notch inhibition.

Biol Reprod. 2009 Oct 28;
Kuokkanen S, Chen B, Ojalvo L, Benard L, Santoro N, Pollard JW

MicroRNAs (miRNAs), a class of small non-coding RNAs that regulate gene expression play fundamental roles in biological processes, including cell differentiation and proliferation. These small molecules mainly direct either target mRNA degradation or translational repression, thereby functioning as gene silencers. Epithelial cells of the uterine lumen and glands undergo cyclic changes under the influence of sex steroid hormones, E2 and P4. Because the expression of miRNAs in the human endometrium has been established, it is important to understand whether miRNAs have a physiological role in modulating the expression of hormonally induced genes. The studies herein establish concomitant differential miRNA and mRNA expression profiles of uterine epithelial cells purified from endometrial biopsies in the late proliferative and mid-secretory phase. Bioinformatics analysis of the differentially expressed mRNAs revealed the cell cycle as the most significantly enriched pathway in the late proliferative phase endometrial epithelium (P = 5.7 x10(-15)). In addition, the Wnt signaling pathway was enriched in proliferative phase. The twelve miRNAs (MIR29B, MIR29C, MIR30B, MIR30D, MIR31, MIR193A-3B, MIR203, MIR204, MIR200C, MIR210, MIR582-5p, and MIR345) whose expression was significantly upregulated in the mid-secretory phase samples were predicted to target many cell cycle genes. Consistent with the role of miRNAs in suppressing their target mRNA expression, the transcript abundance of the predicted targets, including cyclins and cyclin-dependent kinases as well as E2F3 (a known target of MIR210), was decreased. Thus, our findings suggest a role for miRNAs in down regulating the expression of some cell cycle genes in the secretory phase endometrial epithelium, thereby suppressing cell proliferation.

Biomed Pharmacother. 2009 Oct 26;
Thiago LS, Costa ES, Lopes DV, Otazu IB, Nowill AE, Mendes FA, Portilho DM, Abreu JG, Mermelstein CS, Orfao A, Rossi MI, Borojevic R

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children. The Wnt signaling pathway has been found to be extensively involved in cancer onset and progression but its role in BCP-ALL remains controversial. We evaluate the role of the Wnt pathway in maintenance of BCP-ALL cells and resistance to chemotherapy. Gene expression profile revealed that BCP-ALL cells are potentially sensitive to modulation of Wnt pathway. Nalm-16 and Nalm-6 cell lines displayed low levels of canonical activation, as reflected by the virtually complete absence of total beta-catenin in Nalm-6 and the beta-catenin cell membrane distribution in Nalm-16 cell line. Canonical activation with Wnt3a induced nuclear beta-catenin translocation and led to BCP-ALL cell death. Lithium chloride (LiCl) also induced a cytotoxic effect on leukemic cells. In contrast, both Wnt5a and Dkk-1 increased Nalm-16 cell survival. Also, Wnt3a enhanced the in vitro sensitivity of Nalm-16 to etoposide (VP-16) while treatment with canonical antagonists protected leukemic cells from chemotherapy-induced cell death. Overall, our results suggest that canonical activation of the Wnt pathway may exerts a tumor suppressive effect, thus its inhibition may support BCP-ALL cell survival.

Pediatr Dev Pathol. 2009 Oct 19;
Pusantisampan T, Sangkhathat S, Kanngurn S, Kayasut K, Jaruratanasirikul S, Chotsampancharoan T, Kritsaneepaiboon S

Abstract A role of beta-catenin (CTNNB1) in the molecular pathogenesis of adrenocortical carcinoma (ACC) has been suspected in adult ACC and pediatric pigmented nodular adrenocortical disease, but has never been reported in pediatric ACC. We present the case of a 4-month old Thai infant who had Cushing's syndrome secondary to bilateral adrenal tumors with hepatic metastasis. The child was successfully treated with a bilateral adrenalectomy and wedge resection of the liver nodule. Histopathology revealed bilateral adrenocortical tumors with different histologic grades; the right tumor had a higher score, according to modified Weiss criteria. On molecular study, a deletion mutation of beta-catenin involving codons 44-45 was detected in the right adrenal tumor. The same mutation was found in peripheral blood before treatment, which disappeared after the tumor removal. The left tumor harbored wild-type beta-catenin. Immunohistochemistry showed nuclear accumulation of beta-catenin on the right adrenal tumor and the metastatic nodule. In summary, we present evidence that supports the role of the Wnt-signaling pathway in the carcinogenesis of pediatric adrenorcortical carcinoma.

PLoS One. 2009; 4(10): e7650
Samuel LJ, Latinkić BV

BACKGROUND: Cardiac induction, the first step in heart development in vertebrate embryos, is thought to be initiated by anterior endoderm during gastrulation, but what the signals are and how they act is unknown. Several signaling pathways, including FGF, Nodal, BMP and Wnt have been implicated in cardiac specification, in both gain- and loss-of-function experiments. However, as these pathways regulate germ layer formation and patterning, their specific roles in cardiac induction have been difficult to define. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the mechanisms of cardiac induction directly we devised an assay based on conjugates of anterior endoderm from early gastrula stage Xenopus embryos as the inducing tissue and pluripotent ectodermal explants as the responding tissue. We show that the anterior endoderm produces a specific signal, as skeletal muscle is not induced. Cardiac inducing signal needs up to two hours of interaction with the responding tissue to produce an effect. While we found that the BMP pathway was not necessary, our results demonstrate that the FGF and Nodal pathways are essential for cardiogenesis. They were required only during the first hour of cardiogenesis, while sustained activation of ERK was required for at least four hours. Our results also show that transient early activation of the Wnt/beta-catenin pathway has no effect on cardiogenesis, while later activation of the pathway antagonizes cardiac differentiation. CONCLUSIONS/SIGNIFICANCE: We have described an assay for investigating the mechanisms of cardiac induction by anterior endoderm. The assay was used to provide evidence for a direct, early and transient requirement of FGF and Nodal pathways. In addition, we demonstrate that Wnt/beta-catenin pathway plays no direct role in vertebrate cardiac specification, but needs to be suppressed just prior to differentiation.

Cancer Prev Res (Phila Pa). 2009 Nov; 2(11): 915-8
Rodenberg JM, Brown PH

This perspective on Murillo et al. (beginning on page 942 in this issue of the journal) examines the potential of the naturally derived agent deguelin to prevent mammary tumorigenesis. These investigators showed that deguelin inhibits Wnt/beta-catenin signaling in breast cancer cell lines, in addition to inhibiting other previously reported signaling pathways. Our growing understanding of deguelin mechanisms could lead to important advances in the prevention of estrogen receptor-negative breast and other cancers.

Cancer Prev Res (Phila Pa). 2009 Nov; 2(11): 942-50
Murillo G, Peng X, Torres KE, Mehta RG

An emphasis in early detection and more effective treatments has decreased the mortality rate of breast cancer. Despite this decrease, breast cancer continues to be the leading cause of death among women between 40 and 55 years of age and is the second overall cause of death among women. Hence, the aim of the present study was to assess the therapeutic efficacy of deguelin, a rotenoid isolated from several plant species, which has been reported to have chemopreventive and/or chemotherapeutic effects in skin, mammary, colon, and lung cancers. The effect of deguelin on cell proliferation was evaluated using four human breast carcinoma cell lines (MCF-7, BT474, T47D, and MDA-MB-231) by cell count and MTT. Moreover, apoptosis was evaluated by acridine/ethidium staining and DNA laddering. Gene expression changes following deguelin treatment in MDA-MB-231 cells was assessed through microarray analysis. Deguelin at 1 mumol/L was found to inhibit the growth of the breast cancer cell lines tested with a range of 37% to 87%. The highest inhibition was noted for the MDA-MB-231 cell line (MDA-MB-231>BT474>MCF7>T47D>MCF12F). An arrest at the S phase of the cell cycle and apoptosis were shown in the MDA-MB-231 cells treated with deguelin. The microarray profile indicated differential expression of two independent pathways, including clusters of apoptosis and Wnt/beta-catenin signaling genes in cells as a result of deguelin treatment. These studies support the antiproliferative effects of deguelin in human breast cancer cells and, perhaps more importantly, illustrate novel actions by deguelin in the Wnt signaling pathway.

Mech Dev. 2009 Oct 24;
Varnat F, Zacchetti G, Altaba AR

Several lines of evidence point to the central role of Wnt signaling in the initiation of intestinal tumorigenesis, most often due to loss of APC, a negative regulator of the Wnt-betaCATENIN/TCF pathway. Modeling human colon cancers in mice through loss of Apc has shown that inappropriate activation of Wnt signaling is sufficient to induce adenoma formation. More recent analyses have also demonstrated a key role for HEDGEHOG-GLI (HH-GLI) signaling in human colon cancers. However, how the Wnt and HH pathways interact during intestinal development, homeostasis and cancer is not clear. Marker analyses suggest predominant paracrine signaling from rare Shh producing cells in the crypt's bottom to adjacent Gli1(+) mesenchymal cells in normal adult mice. Using conditional KO models, we show that inhibition of the function of the critical Hh mediator Smoothened (Smo) rescues the lethality and intestinal phenotypes of loss of Apc. The results uncover an essential role of the Hh pathway in tumors induced by hyperactive Wnt signaling, suggest the action of the Hh pathway in parallel or downstream of Wnt signaling, and validate this model for its use in preclinical work testing Hh pathway antagonists.

Endocr Metab Immune Disord Drug Targets. 2009 Dec 1;
Ng KW

Anti-resorptives that prevent osteoclasts from resorbing bone are the mainstay of treatment for osteoporosis, while parathyroid hormone is the only agent available that stimulates osteoblasts to form bone. Advances in knowledge about metabolic pathways in bone cell biology have identified specific points of intervention whereby formation and function of osteoclasts and osteoblasts can be inhibited or stimulated. The next generation of therapies for osteoporosis may include molecules that antagonize integrin or inhibit Src tyrosine kinase, vacuolar H+-ATPase, chloride channel or cathepsin K, thus preventing osteoclasts from attaching to bone, form a ruffled border, acidify resorption lacunae or digest organic bone matrix. At least some of these may form a novel class of anti-resorptives capable of inhibiting bone resorption without being coupled to inhibition of bone formation. Human and mouse genetics studies demonstrating the pivotal role of the Wnt signaling pathway in bone metabolism have led to the development of strategies to disrupt Wnt signaling in order to increase bone formation. Selective androgen receptor modulators that produce an anabolic effect on muscle and bone without undesirable androgenic side effects can potentially be used to treat osteoporosis, aged-related frailty, muscle wasting disorders and glucocorticoid-induced osteoporosis. Studies involving these molecules are still in either preclinical or early investigational stage, without fracture data. Nonetheless, preliminary results hold the promise that at least some of these new therapies may develop into effective means of treating and preventing osteoporosis. Any new therapy for osteoporosis must take into consideration its safety, efficacy, affordability and specificity of action.

Cancer Invest. 2009 Oct 26;
Wang W, Xue L, Liu H, Wang P, Xu P, Cai Y

ABSTRACT Inhibition of Wnt/beta-catenin pathway is an attractive method for therapy of various tumors including breast, colorectal, and cervical cancer, etc. However, little is known about the role of Wnt2/beta-catenin pathway in esophageal squamous cell carcinoma (ESCC). Here we identify that Wnt2/beta-catenin signaling pathway is activated in ESCC cells, and sodium nitroprusside (SNP) and siRNA against beta-catenin not only inhibit the expressions of beta-catenin and its major downstream effectors including c-myc and cyclin D1, but induce cell cycle arrest and apoptosis, suggesting that Wnt2/beta-catenin pathway may be a potential molecular target for ESCC therapy.