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Dickkopf AND Wnt

Leilei Zhong, Xiaobin Huang, Emilie Dooms Rodrigues, Jeroen Leijten, Theo Verrips, Mohamed El Khattabi, Marcel Karperien, Janine N Post
Hypertrophic differentiation occurs during in vitro chondrogenesis of mesenchymal stem cells (MSCs), decreasing the quality of the cartilage construct. Previously we identified WNT pathway antagonists Dickkopf 1 homolog (DKK1) and frizzled-related protein (FRZB) as key factors in blocking hypertrophic differentiation of hMSCs. In this study, we investigated the role of endogenously expressed DKK1 and FRZB in chondrogenesis of hMSC, chondrocyte redifferentiation and in preventing cell hypertrophy using three relevant human cell based systems, isolated hMSCs, isolated primary human chondrocytes (hChs), and co-cultures of hMSCs with hChs for which we specifically designed neutralizing nano-antibodies...
October 12, 2016: Stem Cells and Development
Maria Felicia Faienza, Annamaria Ventura, Maurizio Delvecchio, Anna Fusillo, Laura Piacente, Gabriella Aceto, Graziana Colaianni, Silvia Colucci, Luciano Cavallo, Maria Grano, Giacomina Brunetti
CONTEXT: Childhood type 1 diabetes (T1DM) is associated with decreased bone mass. Sclerostin and dickkopf-1 (DKK-1) are Wnt inhibitors which regulate bone formation. OBJECTIVE: To evaluate sclerostin and DKK-1 levels in TD1M children and to analyze the influence of the glycaemic control on bone health. DESIGN AND SETTING: Cross-sectional study conducted at a clinical research center. Partecipants: One hundred and six T1DM subjects (12.2 ± 4 years), 66 on multiple daily injections (MDI) and 40 on continuous subcutaneous infusion of insulin (CSII), and 80 controls...
October 12, 2016: Journal of Clinical Endocrinology and Metabolism
Giuseppina Federico, Michael Meister, Daniel Mathow, Gunnar H Heine, Gerhard Moldenhauer, Zoran V Popovic, Viola Nordström, Annette Kopp-Schneider, Thomas Hielscher, Peter J Nelson, Franz Schaefer, Stefan Porubsky, Danilo Fliser, Bernd Arnold, Hermann-Josef Gröne
Renal tubular atrophy and interstitial fibrosis are common hallmarks of etiologically different progressive chronic kidney diseases (CKD) that eventually result in organ failure. Even though these pathological manifestations constitute a major public health problem, diagnostic tests, as well as therapeutic options, are currently limited. Members of the dickkopf (DKK) family, DKK1 and -2, have been associated with inhibition of Wnt signaling and organ fibrosis. Here, we identify DKK3 as a stress-induced, tubular epithelia-derived, secreted glycoprotein that mediates kidney fibrosis...
January 21, 2016: JCI Insight
Kalliopi Klavdianou, Stamatis-Nick Liossis, Lazaros Sakkas, Dimitrios Daoussis
BACKGROUND: Dickkopf-1 (Dkk-1) is a soluble inhibitor of the canonical Wnt pathway, which plays critical roles in embryonic development. Evidence suggests that this molecule regulates several aspects of both bone biology and fibrosis. OBJECTIVES: To provide an overview of our current knowledge of the role of Dkk-1 in joint remodeling and fibrosis. METHODS: We performed an electronic search (Medline) using the following key words: Dickkopf-1 (or Dkk-1), new bone formation, joint remodeling, ankylosing spondylitis, systemic sclerosis (or scleroderma), and fibrosis, supplemented by a manual search of references from retrieved articles...
August 23, 2016: Seminars in Arthritis and Rheumatism
Jung-Hoo Hwang, Jong Cheon Joo, Dae Joon Kim, Eunbi Jo, Hwa-Seung Yoo, Kyung-Bok Lee, Soo Jung Park, Ik-Soon Jang
Constitutive activation of extracellular signal regulated kinase (ERK)-Jun NH2-terminal kinase (JNK) signaling commonly occurs in tumors. The activation of ERK promotes cell proliferation, whereas that of JNK induces cell apoptosis. However, the apoptotic mechanism of ERK-JNK signaling in cancer is not well understood. Recently, we identified that apoptosis and activation of the JNK signaling pathway were induced after cordycepin treatment in human renal cancer, suggesting that JNK signaling might contribute to TK-10 cell apoptosis...
2016: American Journal of Cancer Research
Chi-Hin Wong, You-Jia Li, Yang-Chao Chen
Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC...
August 21, 2016: World Journal of Gastroenterology: WJG
Aude Marzo, Soledad Galli, Douglas Lopes, Faye McLeod, Marina Podpolny, Margarita Segovia-Roldan, Lorenza Ciani, Silvia Purro, Francesca Cacucci, Alasdair Gibb, Patricia C Salinas
Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer's disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-β-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored...
October 10, 2016: Current Biology: CB
S Ray, T El Khassawna, U Sommer, U Thormann, N D Wijekoon, K Lips, C Heiss, V Alt
Wnt/β-catenin signalling components was shown to affect bone cells function including chondrocytes.Secreted Dkk1, a potent osteogenesis inhibiting factor mediates bone loss in diseased bones by suppressing the biological actions of Wnt proteins. In addition, increased Dkk1 signalling inhibits chondrogenesis in new bone formation. Recent findings also show there exists a cross-talk between the chondrocytes and the cells of the osteoblast lineage, which are the most affected cell types in muskuloskeletal disorders...
August 31, 2016: Journal of Microscopy
Yu Chen, Zi-Feng Chen, Fan He
OBJECTIVE: To understand the mechanism by which tenascin-C regulates osteoblast differentiation and the role of tenascin-C in osteoporosis. METHODS: Tenascin-C protein expression in femoral spongy bone of mice with or without osteoporosis was analyzed using Western blotting. In MC3T3-E1 osteoblasts with or without tenascin-C depletion by a specific siRNA targeting tenascin-C, alkaline phosphatase activity and Dickkopf-1 (DKK-1) expression were determined using quantitative RT-PCR and Western blotting, and the transcriptional activity of Wnt signaling pathway was analyzed using a luciferase reporter assay...
August 20, 2016: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Xin-Wei He, En Wang, Yu-Yan Bao, Feng Wang, Ming Zhu, Xiao-Fei Hu, Xiao-Ping Jin
BACKGROUND AND AIMS: Sclerostin and Dickkopf-1 (Dkk-1) are potent antagonists of Wnt signalling and might therefore play important roles in cardiovascular disease. We investigated whether serum sclerostin and Dkk-1 levels are associated with acute ischaemic stroke and specific stroke subtypes. METHODS: Serum levels of sclerostin and Dkk-1 were measured by ELISA on day 1 and on day 6 after stroke in 62 patients with large artery atherosclerotic (LAA) stroke, on day 1 after stroke in 62 age- and gender-matched patients with small-artery occlusion (SAO) stroke and on admission in 62 healthy controls...
October 2016: Atherosclerosis
Hongxia Zhang, Weili Luo, Yonghong Sun, Yanchun Qiao, Liying Zhang, Zhilian Zhao, Shijun Lv
Increasing studies identified podocyte injury as a key early risk factor resulting in diabetic nephropathy (DN). The ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) participates in podocyte differentiation and injury, which is elevated in the podocytes of a variety of nephritis. Whether UCH-L1 expression is positively related to podocyte injury of DN remains unclear. In this study, elevated expression of UCH-L1 and its intrinsic mechanism in high glucose (HG)-stimulated murine podocytes were investigated using western blot and real-time quantitative PCR...
2016: International Journal of Molecular Sciences
Li-Ye Sun, Zi-Dong Bie, Chuan-Huan Zhang, Hua Li, Liu-Dong Li, Jun Yang
Excessive proliferation of cardiac fibroblasts (CFs) and their transdifferentiation into myofibroblasts leads to expression of α-smooth muscle actin (α-SMA), as well as excessive synthesis and secretion of collagens. This process represents an important pathological basis for myocardial fibrosis (MF). MicroRNA (miR)-154 and the Wnt signaling pathway play key roles in the above process, although their specific interactions are poorly understood. After transfecting CFs with miR-154 mimics or inhibitors, miR-154 was found to inhibit the expression of Dickkopf-related protein 2 (DKK2), while miR-154 inhibitors upregulated DKK2 expression in a western blot analysis...
August 20, 2016: Cell Biology International
F Linke, M Harenberg, M M Nietert, S Zaunig, F von Bonin, A Arlt, M Szczepanowski, H A Weich, S Lutz, C Dullin, P Janovská, M Krafčíková, L Trantírek, P Ovesná, W Klapper, T Beissbarth, F Alves, V Bryja, L Trümper, J Wilting, D Kube
The interaction between vascular endothelial cells (ECs) and cancer cells is of vital importance to understand tumor dissemination. A paradigmatic cancer to study cell-cell interactions is classical Hodgkin Lymphoma (cHL) owing to its complex microenvironment. The role of the interplay between cHL and ECs remains poorly understood. Here we identify canonical WNT pathway activity as important for the mutual interactions between cHL cells and ECs. We demonstrate that local canonical WNT signaling activates cHL cell chemotaxis toward ECs, adhesion to EC layers and cell invasion using not only the Wnt-inhibitor Dickkopf, tankyrases and casein kinase 1 inhibitors but also knockdown of the lymphocyte enhancer binding-factor 1 (LEF-1) and β-catenin in cHL cells...
October 4, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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
Wei Zhang, Shengdong Wang, Houfa Yin, Erman Chen, Deting Xue, Qiang Zheng, Xiang Gao, Zhijun Pan
Substantial evidence has demonstrated that the decreased osteogenic differentiation of bone mesenchymal stem cells (BMSCs) is closely related to bone metabolic diseases. Thus, it is very important to develop several potentially useful therapeutic agents to enhance BMSC osteogenesis. Flavonoids show promise in enhancing bone mass. Dihydromyricetin (DMY), a type of flavonoid, has not yet been investigated regarding its effects on BMSC osteogenesis. To investigate the effects of DMY on osteogenesis, human BMSCs were induced with or without DMY...
July 29, 2016: Fundamental & Clinical Pharmacology
Harun Erdal, Özlem Gül Utku, Eylem Karatay, Bülent Çelik, Şehri Elbeg, İbrahim Doğan
BACKGROUND/AIMS: The Wnt/ß-catenin pathway plays a prominent role in hepatocellular carcinoma (HCC). The Dickkopf (DKK) proteins (DKK1-4) are known Wnt antagonists; the overexpression of DKK1 has been demonstrated in HCC, and increased DKK3 methylation in the HCC tissue is associated with worse prognosis. Thus, the aim of our study was to demonstrate the diagnostic accuracy of serum DKK1 and DKK3 in HCC in comparison with that of serum alpha-fetoprotein (AFP). MATERIALS AND METHODS: We included consecutive 40 HCC patients, 54 cirrhosis patients, and 39 healthy controls...
July 2016: Turkish Journal of Gastroenterology: the Official Journal of Turkish Society of Gastroenterology
Yukihiko Sakisaka, Sousuke Kanaya, Takashi Nakamura, Masato Tamura, Hidetoshi Shimauchi, Eiji Nemoto
Wnt3a is a secreted glycoprotein that activates the glycogen synthase kinase-3β (GSK3β)/β-catenin signaling pathway through low-density-lipoprotein receptor-related protein (LRP)5/6 co-receptors. Wnt3a has been implicated in periodontal development and homeostasis, as well as in cementum formation. Recently, we have reported that Wnt3a increases alkaline phosphatase expression through the induction of osterix (Osx) expression in dental follicle cells, a precursor of cementoblasts. However, the molecular mechanism by which Wnt3a induces Osx expression is still unknown...
September 16, 2016: Biochemical and Biophysical Research Communications
Jinzi Zhou, Jian Jiang, Shuhong Wang, Xiaobo Xia
Retinal pigment epithelial (RPE) cells play important roles in diabetic retinopathy (DR). Dickkopf 1 (DKK1) has been reported to be important in the regulation of cell proliferation and migration. However, there are few previous studies regarding DKK1 in RPE cells. Therefore, in the present study, we investigated the effect of DKK1 on the proliferation and migration of human RPE cells, and the signaling mechanisms underlying these effects. The results showed that the overexpression of DKK1 significantly inhibited the proliferation and migration of ARPE-19 cells...
August 2016: Experimental and Therapeutic Medicine
Yanmei Xu, Xia Li, Hongtao Wang, Pengmu Xie, Xun Yan, Yu Bai, Tingguo Zhang
Aberrant epigenetic modification is associated with the development and progression of cancer. Hypermethylation of tumor suppressor gene promoters and cooperative histone modification have been considered to be the primary mechanisms of epigenetic modification. Ovary granulosa cell tumors (GCTs) are relatively rare, accounting for ~3% of all ovarian malignancies. The present study assessed hypermethylation of the cadherin 13 (CDH13), dickkopf WNT signaling pathway inhibitor 3 (DKK3) and forkhead box L2 (FOXL2) promoters in 30 GCT tissues and 30 healthy control tissues using methylation-specific polymerase chain reaction analysis...
September 2016: Molecular Medicine Reports
Wei Xu, Kuan Pang, Ze-Guang Zhou, Yi-Feng Chen, Ting Mo, Ming Li, Cheng-Bei Liu
Wnt/β-catenin signaling dysregulation is involved in tumorigenesis. Furthermore, epigenetic modification of the Dickkopf (DKK) family (DKK1‑4) has been shown to be important in the regulation of Wnt signaling. However, the functions and mechanism of DKK2 in the development and progression of prostate cancer remain unclear. Therefore, the present study investigated the role of DKK2 in prostate cancer. The mRNA and protein expression levels of DKK2 in prostate cancer tissues and cells were assessed by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively...
September 2016: Molecular Medicine Reports
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