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Logan Horne, Frank R Avilucea, Huifeng Jin, Jared J Barrott, Kyllie Smith-Fry, Yanliang Wang, Bang H Hoang, Kevin B Jones
Previous reports document expression of low-density lipoprotein receptor-related protein 5 (LRP5) in osteosarcoma (OS) tissue. Expression of this Wnt receptor correlated with metastatic disease and poor disease-free survival. Forced expression of dominant-negative LRP5 (dnLRP5), which lacks the membrane binding domain of the native protein and therefore functions as a soluble receptor-sponge for Wnt ligands, reduced in vitro cellular invasion and in vivo xenograft tumor growth for osteosarcoma cell lines. Here, we use a genetically engineered mouse model of osteosarcomagenesis with and without expression of dnLRP5 to assess to what degree tumorigenesis is affected and whether Wnt/β-catenin signaling is circumvented or maintained...
October 2016: Translational Oncology
Alana M Chin, Yu-Hwai Tsai, Stacy R Finkbeiner, Melinda S Nagy, Emily M Walker, Nicole J Ethen, Bart O Williams, Michele A Battle, Jason R Spence
Much of our understanding about how intestinal stem and progenitor cells are regulated comes from studying the late fetal stages of development and the adult intestine. In this light, little is known about intestine development prior to the formation of stereotypical villus structures with columnar epithelium, a stage when the epithelium is pseudostratified and appears to be a relatively uniform population of progenitor cells with high proliferative capacity. Here, we investigated a role for WNT/β-CATENIN signaling during the pseudostratified stages of development (E13...
October 6, 2016: Stem Cell Reports
M Borrell-Pages, G Vilahur, J C Romero, L Casaní, M T Bejar, L Badimon
LRP5 (low-density lipoprotein receptor-related protein 5) activates canonical Wnt signalling. LRP5 plays multiple roles including regulation of lipoprotein and cholesterol homeostasis as well as innate immunity cell function. However, it is not known whether LRP5 has a role in the myocardium. The aim of this study was to investigate LRP5 and Wnt signalling in myocardial remodelling after acute myocardial infarction (MI). Wnt protein levels were determined in a hypercholesterolemic porcine model of MI, in Lrp5 (-/-) C57Bl6 mice, in cultured cardiomyocytes and in human explanted hearts with previous MI episodes...
November 2016: Basic Research in Cardiology
Ying Wang, Yongjun Zhang, Meiyu Fang, Wenglong Bao, Dehou Deng
This study investigated the effect of single-nucleotide polymorphisms (SNPs) of low-density lipoprotein receptor-related protein 5 (LRP5) on the risk of developing non-small cell lung cancer (NSCLC). A total of 500 NSCLC patients and 500 healthy controls were recruited for genotyping of 11 SNPs of LRP5. The association between genotype and NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses. Eleven Tag SNPs were detected...
October 2016: Oncology Letters
Rafael Escate, Teresa Padro, Maria Borrell-Pages, Rosa Suades, Rosa Aledo, Pedro Mata, Lina Badimon
Familial hypercholesterolaemia (FH) is a major risk for premature coronary heart disease due to severe long-life exposure to high LDL levels. Accumulation of LDL in the vascular wall triggers atherosclerosis with activation of the innate immunity system. Here, we have investigated (i) gene expression of LDLR and LRPs in peripheral blood cells (PBLs) and in differentiated macrophages of young FH-patients; and (ii) whether macrophage from FH patients have a differential response when exposed to high levels of atherogenic LDL...
September 29, 2016: Journal of Cellular and Molecular Medicine
Joseph A Sennello, Alexander V Misharin, Annette S Flozak, Sergejs Berdnikovs, Paul Cheresh, John Varga, David W Kamp, G R Scott Budinger, Cara J Gottardi, Anna P Lam
Previous studies established that attenuating Wnt/β-catenin signaling limits lung fibrosis in the bleomycin mouse model of this disease, but the contribution of this pathway to distinct lung cell phenotypes relevant to tissue repair and fibrosis remains incompletely understood. Using microarray analysis, we found that bleomycin-injured lungs from mice that lack the Wnt co-receptor Lrp5 and exhibit reduced fibrosis, showed enrichment for pathways related to extracellular matrix processing, immunity, and lymphocyte proliferation, suggesting the contribution of an immune-matrix remodeling axis relevant to fibrosis...
September 26, 2016: American Journal of Respiratory Cell and Molecular Biology
M Chen, Q R Dong, Q Huang, W Xu, C She
Objective: To investigate the molecular mechanism of low-dose X-ray irradiation on osteoblasts by detecting the gene expression profiles of osteoblasts radiated with 0.5 Gy X-ray. Methods: Microarray analyses to value the changes of gene expression of MC3T3-E1 osteoblasts after 0.5 Gy X-ray irradiation were conducted.The end points included modulation of key markers, and pathway and gene ontology through transcriptomic profiling and bioinformatics analysis. Several major genes during osteoblasts differentiation were selected for Real-time PCR analysis...
September 6, 2016: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Nobuaki Ozeki, Naoko Hase, Naoya Higuchi, Taiki Hiyama, Hideyuki Yamaguchi, Rie Kawai, Toru Matsumoto, Kazuhiko Nakata, Makio Mogi
While human induced pluripotent stem (hiPS) cells have potential use in regenerative medicine, there are no reports on odontoblastic differentiation of hiPS cells. In the current study, to examine integrin profiles and explore the early signaling cascade of odontoblastic differentiation in hiPS cells, we investigated the regulation of autophagy-related gene (Atg) and wingless/int1 (Wnt) signaling in gelatin scaffold (GS) combined with bone morphogenetic protein (BMP)-4 (GS/BMP-4)-mediated odontoblastic differentiation...
September 15, 2016: Differentiation; Research in Biological Diversity
Travis A Burgers, Juan F Vivanco, Juraj Zahatnansky, Andrew J Vander Moren, James J Mason, Bart O Williams
Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density...
2016: Bone Research
M Gong, S Antony, R Sakurai, J Liu, M Iacovino, V K Rehan
OBJECTIVE: Although intrauterine nutritional stress is known to result in offspring obesity and metabolic phenotype, the underlying cellular/molecular mechanisms remain incompletely understood. We tested the hypothesis that compared to the controls, the bone marrow-derived mesenchymal stem cells (BMSCs) of the intrauterine growth restricted (IUGR) offspring exhibit to a more adipogenic phenotype. METHODS: A well-established rat model of maternal food restriction (MFR), i...
September 7, 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Miso Jeon, Naimur Rahman, Yong-Sik Kim
The canonical Wnt/β-catenin signaling not only features in many developmental processes but also recently emerged as an attractive negative regulator of differentiation of preadipocytes into adipocytes. Here, we show that β-catenin signaling plays a distinct role in methyl gallate (MG)-mediated inhibition of 3T3-L1 adipocytes differentiation. We found that the expression of β-catenin decreased after adipogenic hormonal induction, whereas incubation of the differentiating cells with a physiological concentration of MG during adipogenic hormonal induction significantly prevented β-catenin degradation by activating Wnt signaling components such as Wnt1, Wnt10b, Fzd1, Fzd2, Lrp5, Lrp6, Dvl1, and Dvl2...
October 7, 2016: Biochemical and Biophysical Research Communications
Anong Kitjaroentham, Hathairad Hananantachai, Benjaluck Phonrat, Sangchai Preutthipan, Rungsunn Tungtrongchitr
BACKGROUND: Osteoporosis, characterized by low bone mineral density (BMD) and high bone fracture risk, is prevalent in Thai menopausal women. Genetic factors are known to play a key role in BMD. Low density lipoprotein receptor-related protein 5 (LRP5), a co-receptor in the Wnt/beta-catenin pathway, is involved in many aspects of bone biology. As coding single nucleotide polymorphisms (cSNPs) of LRP5, including A1330V (rs3736228), and Asian-related Q89R (rs41494349) and N740N (rs2306862), are associated with lowered BMD, this study aimed to determine the relationship between these LRP5 polymorphisms and BMD in 277 Thai menopausal women...
2016: Journal of Negative Results in Biomedicine
Marissa A H den Hoed, Saskia M F Pluijm, Lisette Stolk, André G Uitterlinden, Rob Pieters, Marry M van den Heuvel-Eibrink
PURPOSE: Despite similarities in upfront treatment of childhood cancer, not every adult survivor of childhood cancer (CCS) has an impaired bone mineral density (BMD). No data are available on the role of genetic variation on impairment of BMD in CCS. METHODS: This cross-sectional single-center cohort study included 334 adult CCSs (median follow-up time after cessation of treatment: 15 years; median age at follow-up: 26 years). Total body BMD (BMDTB ) and lumbar spine BMD (BMDLS ) were measured by dual x-ray absorptiometry...
August 31, 2016: Pediatric Blood & Cancer
Luc Chouinard, Melanie Felx, Nacera Mellal, Aurora Varela, Peter Mann, Jacquelin Jolette, Rana Samadfam, Susan Y Smith, Kathrin Locher, Sabina Buntich, Michael S Ominsky, Ian Pyrah, Rogely Waite Boyce
Romosozumab is a humanized immunoglobulin G2 monoclonal antibody that binds and blocks the action of sclerostin, a protein secreted by the osteocyte and an extracellular inhibitor of canonical Wnt signaling. Blockade of sclerostin binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) allows Wnt ligands to activate canonical Wnt signaling in bone, increasing bone formation and decreasing bone resorption, making sclerostin an attractive target for osteoporosis therapy. Because romosozumab is a bone-forming agent and an activator of canonical Wnt signaling, questions have arisen regarding a potential carcinogenic risk...
August 26, 2016: Regulatory Toxicology and Pharmacology: RTP
V Boschert, C Frisch, J W Back, K van Pee, S E Weidauer, E-M Muth, P Schmieder, M Beerbaum, A Knappik, P Timmerman, T D Mueller
The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up...
August 2016: Open Biology
Edgar S Wills, Wybrich R Cnossen, Joris A Veltman, Rob Woestenenk, Marloes Steehouwer, Jody Salomon, René H M Te Morsche, Meritxell Huch, Jayne Y Hehir-Kwa, Martijn J Banning, Rolph Pfundt, Ronald Roepman, Alexander Hoischen, Joost P H Drenth
Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes...
August 24, 2016: European Journal of Human Genetics: EJHG
Hirohisa Okabe, Jing Yang, Kyle Sylakowski, Mladen Yovchev, Yoshitaka Miyagawa, Shanmugam Nagarajan, Maria Chikina, Michael Thompson, Michael Oertel, Hideo Baba, Satdarshan P Monga, Kari Nichole Nejak-Bowen
: Hepatic repair is directed chiefly by the proliferation of resident mature epithelial cells. Furthermore, if predominant injury is to cholangiocytes, the hepatocytes can transdifferentiate to cholangiocytes to assist in the repair and vice versa, as shown by various fate-tracing studies. However, the molecular bases of reprogramming remain elusive. Using two models of biliary injury where repair occurs through cholangiocyte proliferation and hepatocyte transdifferentiation to cholangiocytes, we identify an important role of Wnt signaling...
August 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Manuela G M Rocha-Braz, Bruno Ferraz-de-Souza
The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e...
August 2016: Archives of Endocrinology and Metabolism
Zhongxiao Wang, Chi-Hsiu Liu, Ye Sun, Yan Gong, Tara L Favazza, Peyton C Morss, Nicholas J Saba, Thomas W Fredrick, Xi He, James D Akula, Jing Chen
Familial exudative vitreoretinopathy (FEVR) is characterized by delayed retinal vascular development, which promotes hypoxia-induced pathologic vessels. In severe cases FEVR may lead to retinal detachment and visual impairment. Genetic studies linked FEVR with mutations in Wnt signaling ligand or receptors, including low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we investigated ocular pathologies in a Lrp5 knockout (Lrp5(-/-)) mouse model of FEVR and explored whether treatment with a pharmacologic Wnt activator lithium could bypass the genetic defects, thereby protecting against eye pathologies...
October 2016: American Journal of Pathology
Matthias Zebisch, Verity A Jackson, Yuguang Zhao, E Yvonne Jones
Kremen 1 and 2 have been identified as co-receptors for Dickkopf (Dkk) proteins, hallmark secreted antagonists of canonical Wnt signaling. We present here three crystal structures of the ectodomain of human Kremen1 (KRM1ECD) at resolutions between 1.9 and 3.2 Å. KRM1ECD emerges as a rigid molecule with tight interactions stabilizing a triangular arrangement of its Kringle, WSC, and CUB structural domains. The structures reveal an unpredicted homology of the WSC domain to hepatocyte growth factor. We further report the general architecture of the ternary complex formed by the Wnt co-receptor Lrp5/6, Dkk, and Krm, determined from a low-resolution complex crystal structure between β-propeller/EGF repeats (PE) 3 and 4 of the Wnt co-receptor LRP6 (LRP6PE3PE4), the cysteine-rich domain 2 (CRD2) of DKK1, and KRM1ECD...
September 6, 2016: Structure
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