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Neuropeptide Y1 Receptor Antagonist but Not Neuropeptide Y Itself Increased Bone Mineral Density When Locally Injected with Hyaluronic Acid in Male Wistar Rats
Turkish Journal of Medical Sciences Turk J Med Sci (2020) 50: 1454-1460 http://journals.tubitak.gov.tr/medical/ © TÜBİTAK Research Article doi:10.3906/sag-2001-268 Neuropeptide Y1 receptor antagonist but not neuropeptide Y itself increased bone mineral density when locally injected with hyaluronic acid in male Wistar rats 1, 2 3 Muhammer Özgür ÇEVİK *, Petek KORKUSUZ , Feza KORKUSUZ 1 Department of Medical Genetics, Faculty of Medicine, Adıyaman University, Adıyaman, Turkey 2 Department of Histology and Embryology, Faculty of Medicine, Hacettepe University, Ankara, Turkey 3 Department of Sports Medicine, Faculty of Medicine, Hacettepe University, Ankara, Turkey Received: 31.01.2020 Accepted/Published Online: 19.05.2020 Final Version: 26.08.2020 Background/aim: The nervous system controls bone mass via both the central (CNS) and the peripheral (PNS) nervous systems. Intriguingly, neuropeptide Y (NPY) signaling occurs in both. Less is known on how the PNS stimulated NPY signaling controls bone metabolism. The objective of this study was to evaluate whether NPY or NPY1 receptor antagonist changes local bone mineral density (BMD) when injected into a Wistar rat tibia. Materials and methods: Tibial intramedullary area of 24 wild type male Wistar rats (average weight = 350 ± 50 g, average age = 4 ± 0.5 months) were injected with NPY (1 × 10-5 M and 1 × 10-6 M) and NPY1 receptor antagonist (1 × 10-4 M) dissolved in hyaluronic acid (HA) separately. Tibiae were collected after one and two weeks. BMD was measured with dual-energy X-ray absorptiometry (DXA) and micro quantitative computer tomography (QCT). Histological changes were analyzed with light microscopy, Goldner's Masson trichrome (MT), and hematoxylin-eosin staining. -
Mechanosensitivity and Mechanotransduction Series: Mechanosensitivity in Cells and Tissues, Vol
A. Kamkin, I. Kiseleva (Eds.) Mechanosensitivity and Mechanotransduction Series: Mechanosensitivity in Cells and Tissues, Vol. 4 ▶ One book provides a detailed description of molecular mechanisms of mechanosensing and mechanotransduction in different cells ▶ One book brings together a comprehensive outline of modern vision of structure and functions of cytoskeleton ▶ Provides a wide and detailed description of various signaling pathways This book presents the latest findings in the field of research of mechanosensitivity and mechanotransduction in different cells and tissues. Mechanosensitivity and mechanotransduction of the heart and vascular cells, in the lung, in bone and joint tissues, in sensor systems and in blood cells are described in detail. This Volume focuses on molecular mechanisms 2011, XXIV, 371 p. of mechanosensitivity and mechanotransduction via cytoskeleton. Integrin-mediated mechanotransduction, the role of actin cytoskeleton and the role of other cytoskeletal elements are discussed. It contains a detailed description of several stretch-induced Printed book signaling cascades with multiple levels of crosstalk between different pathways. It Hardcover contains a description of the role of nitric oxide in regulation of cardiac activity and in ISBN 978-90-481-9880-1 regulation of mechanically gated channels in the heart. In the heart mechanical signals are propagated into the intracellular space primarily via integrin-linked complexes, ▶ 219,99 € | £199.99 and are subsequently transmitted from cell to cell via paracrine signaling. Biochemical ▶ *235,39 € (D) | 241,99 € (A) | CHF 259.50 signals derived from mechanical stimuli activate both acute phosphorylation of signaling cascades, such as in the PI3K, FAK, and ILK pathways, and long-term morphological modii cations via intracellular cytoskeletal reorganization and extracellular matrix remodelling. -
Jdp2 Downregulates Trp53 Transcription to Promote Leukaemogenesis in the Context of Trp53 Heterozygosity
Oncogene (2013) 32, 397 --402 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc SHORT COMMUNICATION Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity L van der Weyden1, AG Rust1,4, RE McIntyre1,4, CD Robles-Espinoza1, M del Castillo Velasco-Herrera1, R Strogantsev2, AC Ferguson-Smith2, S McCarthy1, TM Keane1, MJ Arends3 and DJ Adams1 We performed a genetic screen in mice to identify candidate genes that are associated with leukaemogenesis in the context of Trp53 heterozygosity. To do this we generated Trp53 heterozygous mice carrying the T2/Onc transposon and SB11 transposase alleles to allow transposon-mediated insertional mutagenesis to occur. From the resulting leukaemias/lymphomas that developed in these mice, we identified nine loci that are potentially associated with tumour formation in the context of Trp53 heterozygosity, including AB041803 and the Jun dimerization protein 2 (Jdp2). We show that Jdp2 transcriptionally regulates the Trp53 promoter, via an atypical AP-1 site, and that Jdp2 expression negatively regulates Trp53 expression levels. This study is the first to identify a genetic mechanism for tumour formation in the context of Trp53 heterozygosity. Oncogene (2013) 32, 397--402; doi:10.1038/onc.2012.56; published online 27 February 2012 Keywords: p53; Jdp2; transposon; heterozygosity; lymphoma; mice INTRODUCTION targeted by transposon insertion events leading to upregulated Genetic alterations of TP53 are frequent events in tumourigenesis Jdp2 expression and a decrease in Trp53 expression levels. Further and promote genomic instability, impair apoptosis, and contribute we illustrate that Jdp2 regulates the Trp53 promoter via an atypical to aberrant self-renewal.1--4 The spectrum of mutations that occur AP-1 binding site. -
The Unknown Process Osseointegration
biology Editorial The Unknown Process Osseointegration Nansi López-Valverde , Javier Flores-Fraile and Antonio López-Valverde * Department of Surgery, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; [email protected] (N.L.-V.); j.fl[email protected] (J.F.-F.) * Correspondence: [email protected] Received: 3 July 2020; Accepted: 14 July 2020; Published: 16 July 2020 Abstract: Although it was already described more than fifty years ago, there is yet no in-depth knowledge regarding the process of osseointegration as far as its mechanism of action is concerned. It could be one of the body’s ways of reacting to a foreign body, where the individual’s immune response capacity is involved. It is known that the nervous system has an impact on bone health and that the role of the autonomic nervous system in bone remodeling is an attractive field for current research. In the future, immuno/neuromodulatory techniques will open new and exciting lines of research. Keywords: osseointegration; foreign-body reaction; bone remodeling; immuno/neuromodulatory techniques Although the process of osseointegration was first described by Brånemark and colleagues [1], 50 years later, the real mechanism of this process, remains unknown and has not been studied in depth. The model proposed by Koka and Zarb marked genetics as one of the patient’s inherent variables, necessary, to achieve “sufficient” and lasting results [2]. Among the proposed theories, two have acquired particular interest: “foreign-body reaction”, which interprets osseointegration from the point of view of adverse immune processes [3]; and the so-called by certain authors “brain-bone axis” theory [4]. -
A Dissertation Entitled the Androgen Receptor
A Dissertation entitled The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit Submitted to the Graduate Faculty as partial fulfillment of the requirements for the PhD Degree in Biomedical science Dr. Manohar Ratnam, Committee Chair Dr. Lirim Shemshedini, Committee Member Dr. Robert Trumbly, Committee Member Dr. Edwin Sanchez, Committee Member Dr. Beata Lecka -Czernik, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo August 2011 Copyright 2011, Mesfin Gonit This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit As partial fulfillment of the requirements for the PhD Degree in Biomedical science The University of Toledo August 2011 Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen- independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen. -
Regulatory Networks in Mechanotransduction Reveal Key Genes in Promoting Cancer Cell Stemness and Proliferation
Oncogene (2019) 38:6818–6834 https://doi.org/10.1038/s41388-019-0925-0 ARTICLE Regulatory networks in mechanotransduction reveal key genes in promoting cancer cell stemness and proliferation 1 2 2 1 3 3 1 3,4 Wei Huang ● Hui Hu ● Qiong Zhang ● Xian Wu ● Fuxiang Wei ● Fang Yang ● Lu Gan ● Ning Wang ● 1 2 Xiangliang Yang ● An-Yuan Guo Received: 16 January 2019 / Revised: 21 June 2019 / Accepted: 8 July 2019 / Published online: 12 August 2019 © The Author(s) 2019. This article is published with open access Abstract Tumor-repopulating cells (TRCs) are cancer stem cell (CSC)-like cells with highly tumorigenic and self-renewing abilities, which were selected from tumor cells in soft three-dimensional (3D) fibrin gels with unidentified mechanisms. Here we evaluated the transcriptome alteration during TRCs generation in 3D culture and revealed that a variety of molecules related with integrin/membrane and stemness were continuously altered by mechanical environment. Some key regulators such as MYC/STAT3/hsa-miR-199a-5p, were changed in the TRCs generation. They regulated membrane genes and the downstream mechanotransduction pathways such as Hippo/WNT/TGF-β/PI3K-AKT pathways, thus 1234567890();,: 1234567890();,: further affecting the expression of downstream cancer-related genes. By integrating networks for membrane proteins, the WNT pathway and cancer-related genes, we identified key molecules in the selection of TRCs, such as ATF4, SLC3A2, CCT3, and hsa-miR-199a-5p. Silencing ATF4 or CCT3 inhibited the selection and growth of TRCs whereas reduction of SLC3A2 or hsa-miR-199a-5p promoted TRCs growth. Further studies showed that CCT3 promoted cell proliferation and stemness in vitro, while its suppression inhibited TRCs-induced tumor formation. -
Integrin Signaling Revisited
466 Review TRENDS in Cell Biology Vol.11 No.12 December 2001 Integrin signaling revisited Martin A. Schwartz Adhesion to the extracellular matrix (ECM) is a crucial regulator of cell function, appear to be downstream of FAK and to contribute to and it is now well established that signaling by integrins mediates many of cell migration12,13. The adaptor protein p130cas also these effects. Ten years of research has seen integrin signaling advance on binds to FAK and has been linked to activation of the many fronts towards a molecular understanding of the control mechanisms. small GTPase Rac to promote motility. This diversity of Most striking is the merger with studies of other receptors, the cytoskeleton downstream pathways that converge on cell migration and mechanical forces within the general field of signaling networks. suggests that FAK is a central coordinator of this process. FAK has also been implicated in cell-cycle When I wrote a Trends in Cell Biology review on regulation through activation of both the Erk and integrin signaling in 19921, a 3000-word article could JNK pathways. And FAK plays an important role in cover the entire subject without omitting any key mediating integrin-dependent cell survival, possibly references. In the year 2000 alone, a literature search through phosphoinositide (PI) 3-kinase or JNK7,8,14,15. on ‘integrin’ plus ‘signal transduction’ yielded 480 Multiple physical associations of FAK with references. Given the impossibility of covering more other signaling molecules appear to mediate these than a sliver of what’s been written, I have chosen to multiple effector pathways. -
Biology of Bone Repair
Biology of Bone Repair J. Scott Broderick, MD Original Author: Timothy McHenry, MD; March 2004 New Author: J. Scott Broderick, MD; Revised November 2005 Types of Bone • Lamellar Bone – Collagen fibers arranged in parallel layers – Normal adult bone • Woven Bone (non-lamellar) – Randomly oriented collagen fibers – In adults, seen at sites of fracture healing, tendon or ligament attachment and in pathological conditions Lamellar Bone • Cortical bone – Comprised of osteons (Haversian systems) – Osteons communicate with medullary cavity by Volkmann’s canals Picture courtesy Gwen Childs, PhD. Haversian System osteocyte osteon Picture courtesy Gwen Childs, PhD. Haversian Volkmann’s canal canal Lamellar Bone • Cancellous bone (trabecular or spongy bone) – Bony struts (trabeculae) that are oriented in direction of the greatest stress Woven Bone • Coarse with random orientation • Weaker than lamellar bone • Normally remodeled to lamellar bone Figure from Rockwood and Green’s: Fractures in Adults, 4th ed Bone Composition • Cells – Osteocytes – Osteoblasts – Osteoclasts • Extracellular Matrix – Organic (35%) • Collagen (type I) 90% • Osteocalcin, osteonectin, proteoglycans, glycosaminoglycans, lipids (ground substance) – Inorganic (65%) • Primarily hydroxyapatite Ca5(PO4)3(OH)2 Osteoblasts • Derived from mesenchymal stem cells • Line the surface of the bone and produce osteoid • Immediate precursor is fibroblast-like Picture courtesy Gwen Childs, PhD. preosteoblasts Osteocytes • Osteoblasts surrounded by bone matrix – trapped in lacunae • Function -
Wound Mechanotransduction in Repair and Regeneration Victor W
REVIEW Pushing Back: Wound Mechanotransduction in Repair and Regeneration Victor W. Wong1, Satoshi Akaishi1, Michael T. Longaker1 and Geoffrey C. Gurtner1 Human skin is a highly specialized mechanorespon- These physical interactions regulate key developmental and sive interface separating our bodies from the external homeostatic mechanisms and underlie the tremendous environment. It must constantly adapt to dynamic functional plasticity of skin (Silver et al., 2003; Blanpain physical cues ranging from rapid expansion during and Fuchs, 2009). Although mechanical forces are implicated embryonic and early postnatal development to ubi- in the pathogenesis of numerous diseases (Ingber, 2003a), quitous external forces throughout life. Despite the their role in cutaneous biology remains poorly understood. suspected role of the physical environment in However, the fundamental mechanisms responsible for cutaneous processes, the fundamental molecular mechanotransduction (the conversion of physical stimuli into mechanisms responsible for how skin responds to biochemical responses) are increasingly being elucidated on force remain unclear. Intracellular pathways convert molecular and cellular levels (Ingber, 2006). The ongoing challenge for researchers and clinicians is to fully understand mechanical cues into biochemical responses (in a these mechanotransduction pathways in living organs so that process known as mechanotransduction) via complex they can be translated into clinical therapies. mechanoresponsive elements that often blur the In 1861, the German anatomist Karl Langer published the distinction between physical and chemical signaling. observation that skin exhibits intrinsic tension (Langer K, For example, cellular focal adhesion components 1978), a finding he attributed to the French surgeon Baron exhibit dual biochemical and scaffolding functions Guillaume Dupuytren. Since then, surgeons have adhered to that are critically modulated by force. -
Regulation of Runx2 Accumulation and Its Consequences
Regulation of Runx2 Accumulation and Its Consequences Junko Shimazu Submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2016 ©2016 Junko Shimazu All Rights Reserved ABSTRACT Regulation of Runx2 Accumulation and Its Consequences Junko Shimazu Osteoblasts are bone-forming cells and therefore they are responsible of the synthesis of type I collagen, the main component of bone matrix. However, there is an apparent disconnect between the regulation of osteoblast differentiation and bone formation since the synthesis of Type I collagen precedes the expression of Runx2, the earliest determinant of osteoblast differentiation. Recently, genetic experiments in the mouse have revealed the existence of an unexpected cross-regulation between bone and other organs. In particular this body of work has highlighted the importance of osteoblasts as endocrine cells to regulate whole-body glucose homeostasis by secretion of a hormone, osteocalcin. However, the fundamental question of why bone regulates glucose homeostasis remained to be answered. Therefore, in my thesis, considering that bone is a metabolically demanding organ that constantly renews itself, I hypothesized that characterizing the connection between the need of glucose as a main nutrient in osteoblasts and bone development will provide a key to deeper understanding of why bone regulates glucose homeostasis. My work shows here that glucose uptake through GLUT1 in osteoblasts is needed for osteoblast differentiation by suppressing the AMPK-dependent activation by phosphorylation at S148 of Smurf1 that targets Runx2 for degradation. I also uncovered the mechanism of action of Smurf1 in this setting. -
Estrogen Receptor-Α in Osteocytes Is Important for Trabecular Bone Formation in Male Mice
Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice Sara H. Windahla, Anna E. Börjessona, Helen H. Farmana, Cecilia Engdahla,Sofia Movérare-Skrtica, Klara Sjögrena, Marie K. Lagerquista, Jenny M. Kindbloma, Antti Koskelab, Juha Tuukkanenb, Paola Divieti Pajevicc, Jian Q. Fengd, Karin Dahlman-Wrighte, Per Antonsone, Jan-Åke Gustafssone,f,1,2, and Claes Ohlssona,1,2 aDepartment of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden; bDepartment of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, Oulu 90014, Finland; cDepartment of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114; dDepartment of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX 75246; eDepartment of Biosciences and Nutrition and Center for Biosciences at Novum, Karolinska Institutet, 141 83 Huddinge, Sweden; and fCenter for Nuclear Receptors and Cell Signaling, Department of Cell Biology and Biochemistry, University of Houston, Houston, TX 77204 Contributed by Jan-Åke Gustafsson, December 4, 2012 (sent for review October 25, 2012) The bone-sparing effect of estrogen in both males and females is in osteoclasts is crucial for trabecular bone in females, but it is primarily mediated via estrogen receptor-α (ERα), encoded by the dispensable for trabecular bone in male mice and for cortical Esr1 gene. ERα in osteoclasts is crucial for the trabecular bone- bone in both males and females. However, not only osteoclasts sparing effect of estrogen in females, but it is dispensable for but also osteoblasts/osteocytes express ERs (15–17). -
Supplementary Information
Osa et al Supplementary Information Clinical implications of monitoring nivolumab immunokinetics in previously treated non– small cell lung cancer patients Akio Osa, Takeshi Uenami, Shohei Koyama, Kosuke Fujimoto, Daisuke Okuzaki, Takayuki Takimoto, Haruhiko Hirata, Yukihiro Yano, Soichiro Yokota, Yuhei Kinehara, Yujiro Naito, Tomoyuki Otsuka, Masaki Kanazu, Muneyoshi Kuroyama, Masanari Hamaguchi, Taro Koba, Yu Futami, Mikako Ishijima, Yasuhiko Suga, Yuki Akazawa, Hirotomo Machiyama, Kota Iwahori, Hyota Takamatsu, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Esra A. Akbay, Peter S. Hammerman, Kwok-kin Wong, Glenn Dranoff, Masahide Mori, Takashi Kijima, Atsushi Kumanogoh Supplemental Figures 1 – 8 1 Osa et al Supplemental Figure 1. The frequency of nivolumab-bound T cells was maintained in patients who continued treatment. Nivolumab binding in CD8 and CD4 T cells was analyzed at two follow-up points, as indicated, in fresh peripheral blood from three representative cases from protocol 1 that continued treatment. 2 Osa et al Supplemental Figure 2. Long-term follow-up of nivolumab binding to T cells from fresh whole blood. Nivolumab binding was followed up in fresh peripheral blood from an additional case, Pt.7. 3 Osa et al Supplemental Figure 3. Long-term duration of nivolumab binding is due to sustained circulation of residual nivolumab in plasma. (A) PBMCs acquired from Pt.8 and 9 at pretreatment (pre PBMCs) and after a single dose (post 1 PBMCs) were cultured in regular medium without nivolumab (top and middle). Pre PBMCs were also incubated with 10 µg/ml nivolumab in vitro before the cultures were started (bottom). Nivolumab binding status was monitored at the indicated time points.