DOCSLIB.ORG

Regulation of Bone Remodeling by Parathyroid Hormone

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulation of Bone Remodeling by Parathyroid Hormone Downloaded from http://perspectivesinmedicine.cshlp.org/ at Harvard Library on March 22, 2018 - Published by Cold Spring Harbor Laboratory Press Regulation of Bone Remodeling by Parathyroid Hormone Marc N. Wein and Henry M. Kronenberg Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 Correspondence: [email protected] Parathyroid hormone (PTH) exerts profound effects on skeletal homeostasis through multiple cellular and molecular mechanisms. Continuous hyperparathyroidism causes net loss of bone mass, despite accelerating bone formation by osteoblasts. Intermittent treatment with PTH analogs represents the only Food and Drug Administration (FDA)-approved bone ana- bolic osteoporosis treatment strategy. Functional PTH receptors are present on cells of the osteoblast lineage, ranging from early skeletal stem cells to matrix-embedded osteocytes. In addition, bone remodeling by osteoclasts liberates latent growth factors present within bone matrix. Here, we will provide an overview of the multiple cellular and molecular mechanisms through which PTH influences bone homeostasis. Notably, net skeletal effects of continuous versus intermittent can differ significantly. Where possible, we will highlight mechanisms through which continuous hyperparathyroidism leads to bone loss, and through which in- termittent hyperparathyroidism boosts bone mass. Given the therapeutic usage of intermittent PTH (iPTH) treatment for osteoporosis, particular attention will be paid toward mechanisms underlying the bone anabolic effects of once daily PTH administration. arathyroid hormone (PTH) is a major also been shown to boost bone mass and reduce Pendocrine regulator of extracellular calcium fractures in patients with osteoporosis when giv- and phosphate levels (Gensure et al. 2005). en by once daily subcutaneous injection (Miller Chronic hyperparathyroidism causes net loss et al. 2016). Currently, iPTH/PTHrP treatments of bone mass caused by excessive stimulation represent the only Food and Drug Administra- www.perspectivesinmedicine.org of bone resorption, but also increases osteoblast tion (FDA)-approved osteoporosis medications numbers and bone formation. In contrast, when that stimulate new bone formation. injected once daily, intermittent PTH (iPTH) It is well documented that iPTH treatment amino acids 1–34 (teriparatide) treatment boosts stimulates new bone formation; however, the bone mass, increases bone formation, and re- cellular and molecular mechanisms through duces fractures in at-risk individuals (Silva et al. which this occurs are incompletely understood. 2011). PTH and parathyroid hormone related In addition, two phenomena may significantly peptide (PTHrP) both signal through the same limit the bone-forming efficacy that these Gprotein–coupled receptor (Juppneret al. 1991). medications achieve. First, iPTH concomitantly Recently, the PTHrP analog, abaloparatide, has stimulates bone formation by osteoblasts and Editors: Gerard Karsenty and David T. Scadden Additional Perspectives on Bone: A Regulator of Physiology available at www.perspectivesinmedicine.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a031237 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ at Harvard Library on March 22, 2018 - Published by Cold Spring Harbor Laboratory Press M.N. Wein and H.M. Kronenberg bone resorption by osteoclasts (Silva et al. the osteoblast lineage (Fan et al. 2017). Non- 2011). Therefore, concurrent osteoclast stimula- cell-autonomous effects of PTH on osteoblast tion might mitigate some of the gains in bone activity may also occur through increases in mass that are achieved. Second, the ability of actions of growth factors. For example, PTH- iPTH to stimulate new bone formation wanes induced osteoclastic bone resorption may liber- with time and repeated dosing (Finkelstein ate matrix growth factors that in turn recruit et al. 2009). Progressive blunting of the bone osteoblast progenitors to bone surfaces and anabolic effect of iPTH may also limit efficacy stimulate their differentiation (Wu et al. 2010), of prolonged treatment. and PTH increases the production of a variety of These mysteries and limitations associated growth factors by osteoblasts. T lymphocytes in with iPTH therapy highlight the need to achieve the bone marrow microenvironment respond to a precise understanding of the molecular and iPTH by producing cytokines that stimulate cellular mechanisms underlying its effects in osteoblast differentiation (Pacifici 2013). Osteo- bone (Jilka 2007). Over the past three decades, clasts may generate factors important in increas- several cellular mechanisms have been proposed ing osteoblast numbers (Charles and Aliprantis to explain how iPTH treatment increases bone 2014). Finally, through effects on osteocytes, formation (Table 1). PTH treatment increases PTH reduces levels of the antiosteoblastogenic osteoblast cell number among postmitotic cells WNT inhibitor sclerostin (Keller and Kneissel of the lineage in two ways: PTH significantly 2005), thus providing another paracrine mech- decreases osteoblast apoptosis (Jilka et al. 1999) anism through which PTH might stimulate and activates bone lining cells (Kim et al. osteoblast differentiation. The examples listed 2012). Further, PTH acts directly on early cells here represent just the tip of the iceberg of in the osteoblast lineage. Studies on cultured how PTH uses multiple, complementary mech- bone marrow–derived stromal cells (e.g., Ni- anisms to exert its profound influence on bone. shida et al. 1994), and, more recently, in vivo Here, we will dive deeper into these cellular lineage tracing studies (Balani et al. 2017) have mechanisms, highlighting current knowledge shown these effects. PTH also inhibits adipocyte of the intracellular signaling pathways involved, differentiation of early skeletal stem cells in and major unresolved questions. Table 1. Overview of the cellular mechanisms through which PTH promotes bone formation in PTH receptor- expressing cells Target cell Effects of parathyroid hormone www.perspectivesinmedicine.org Skeletal stem cells Increased numbers of Sox9-labeled stem cells owing to reduced apoptosis Increased Runx2 expression and differentiation of leptin receptor-expressing stem cells Bone marrow stromal Inhibits adipocyte differentiation cells Osteoblasts Reduced osteoblast apoptosis Increased WNT signaling in osteoblasts Bone lining cells Direct conversion into bone-forming osteoblasts T lymphocytes Increased WNT10B expression, which promotes osteoblast activity Increased CD40L expression, which increases OPG expression and promotes marrow stromal cells to become osteoblasts Increased IL-17 expression, which stimulates RANKL expression Osteocytes Reduced SOST expression, which enhances osteoblast activity Increased RANKL expression Increased perilacunar/canalicular remodeling See text for details and references. In addition, PTH used several indirect mechanisms to enhance bone formation and promote skeletal remodeling, as summarized in the text. OPG, Osteoprotegerin; IL, interleukin. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a031237 Downloaded from http://perspectivesinmedicine.cshlp.org/ at Harvard Library on March 22, 2018 - Published by Cold Spring Harbor Laboratory Press Bone Remodeling and Parathyroid Hormone OSTEOBLASTS AS PTH TARGETS for osteoblast differentiation and function (Ducy et al. 1997, 1999). Runx2 protein levels Studies in animal models and humans have in vitro and in vivo are tightly controlled by shown that PTH administration leads to in- Nedd4 family HECT ubiquitin ligases (Ingham creased bone formation through an increase et al. 2004), including Smurf1 and WWP1 in osteoblast number and surface, as well as (Zhao et al. 2003; Jones et al. 2006; Shu et al. an increase in mineralized matrix deposition 2013; Wei et al. 2015; Shimazu et al. 2016). In through effects on proliferation of precursors, osteoblasts, PTH signaling promotes Smurf1- suppression of apoptosis, and activation of lin- driven Runx2 ubiquitin-dependent degradation ing cells (Jilka 2007). However, the predominant (Bellido et al. 2003). Therefore, PTH simultane- direct effect of iPTH on osteoblasts in vivo in- ously inhibits osteoblast apoptosis and drives volves reductions in osteoblast apoptosis rather Runx2 degradation; these opposing actions than increased proliferation of preosteoblasts. may explain why iPTH administration is needed Seminal studies (Jilka et al. 1999) in which os- to elicit net effects that favor osteoblast activity. teoblast apoptosis was carefully quantified using In addition to Bad phosphorylation and reg- TUNEL staining on cancellous bone surfaces ulation of Runx2 stability, multiple additional revealed that iPTH treatment reduces osteoblast target genes in osteoblasts have been proposed apoptosis in vivo. Interestingly, in vivo, anti- to contribute to the antiapoptotic effects of apoptotic effects of iPTH are not necessarily iPTH therapy. Transcriptomic profiling of oste- confined to bone-forming osteoblasts; we oblasts treated with PTH or PTHrP identified (Balani et al. 2017) recently showed that iPTH ephrinB2 as a prominently up-regulated gene treatment also reduces apoptosis of Sox9-la- (Allan et al. 2008). Bidirectional ephrin/Eph beled early skeletal stem cells. As described be- signaling regulates
Load more

Recommended publications
  • Parathyroid Hormone Stimulates Bone Formation and Resorption In
    Proc. Nati. Acad. Sci. USA Vol. 78, No. 5, pp. 3204-3208, May 1981 Medical Sciences Parathyroid hormone stimulates bone formation and resorption in organ culture: Evidence for a coupling mechanism (endocrine/mineralization/bone metabolism/cartilage/regulation) GuY A. HOWARD, BRIAN L. BOTTEMILLER, RUSSELL T. TURNER, JEANNE I. RADER, AND DAVID J. BAYLINK American Lake VA Medical Center, Tacoma, Washington 98493; and Department of Medicine, University of Washington, Seattle, Washington 98195 Communicated by Clement A. Finch, January 26, 1981 ABSTRACT We have developed an in vitro system, using em- growing rats with PTH results in an increase in formation and bryonic chicken tibiae grown in a serum-free medium, which ex- resorption (4) and a net gain in bone volume (10-12). We have hibits simultaneous bone formation and resorption. Tibiae from recently obtained similar results in vitro for the acute and 8-day embryos increased in mean (±SD) length (4.0 ± 0.4 to 11.0 chronic effects of PTH (13). Moreover, as reported earlier for ± 0.3 mm) and dry weight (0.30 ± 0.04 to 0.84 ± 0.04 mg) during resorption in rat bone (14), the in vitro effect of PTH in our 12 days in vitro. There was increased incorporation of [3H]proline system is an inductive one in that the continued presence of into hydroxyproline (120 ± 20 to 340 ± 20 cpm/mg of bone per PTH is unnecessary for bone resorption and bone formation to 24 hr) as a measure of collagen synthesis, as well as a 62 ± 5% increase in total calcium and 45Ca taken up as an indication of ac- be stimulated for several days (13).
    [Show full text]
  • Direct Measurement of Bone Resorption and Calcium
    Proc. Natl. Acad. Sci. USA Vol. 77, No. 4, pp. 1818-1822, April 1980 Biochemistry Direct measurement of bone resorption and calcium conservation during vitamin D deficiency or hypervitaminosis D ([3Hltetracycline/collagen/chicks/growth modeling/kinetics) LEROY KLEIN Departments of Orthopaedics, Biochemistry, and Macromolecular Science, Case Western Reserve University, Cleveland, Ohio 44106 Communicated by Oscar D. Ratnoff, December 20,1979 ABSTRACT When bone is remodeled during the growth of complication, various workers (11, 12) have expressed the need a given size bone to a larger size, some bone is resorbed and for a more direct measurement of bone turnover. In addition, some is deposited. Much of the resorbed bone mineral, calcium, tracer methods for calcium kinetics involve only plasma tracer can be reutilized during bone formation. The net and absolute effects of normal growth, vitamin D deficiency, or vitamin D concentrations and focus on net pool turnover rather than on excess were compared on bone resortion, bone formation, and more absolute measurements of bone turnover (13). calcium reutilization. Growing chic were relabeled exten- Bone resorptiont has been observed directly by using histo- sively with three isotopes: 45Ca, [3Htetracycline, and [3H]pro- logical measurements of the increase in diameter of the bone line. Data were obtained weekly during 3 weeks of control marrow space in rapidly growing rats (14). Resorption has been growth, vitamin D deficiency, or vitamin D overdosage while measured kinetically by either 45Ca under steady-state condi- on a nonradioactive diet. Bone resorption as measured by in- creases in the marrow (inner) diameter of the midshaft of the tions in adult rats (15) or 40Ca dilution of the natural isotope femur and humerus and by the weekly losses of total [3Hjtetra- 48Ca in human subjects (16).
    [Show full text]
  • On the Turning of Xenopus Retinal Axons Induced by Ephrin-A5
    Development 130, 1635-1643 1635 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00386 On the turning of Xenopus retinal axons induced by ephrin-A5 Christine Weinl1, Uwe Drescher2,*, Susanne Lang1, Friedrich Bonhoeffer1 and Jürgen Löschinger1 1Max-Planck-Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany 2MRC Centre for Developmental Neurobiology, King’s College London, New Hunt’s House, Guy’s Hospital Campus, London SE1 1UL, UK *Author for correspondence (e-mail: [email protected]) Accepted 13 January 2003 SUMMARY The Eph family of receptor tyrosine kinases and their turning or growth cone collapse when confronted with ligands, the ephrins, play important roles during ephrin-A5-Fc bound to beads. However, when added in development of the nervous system. Frequently they exert soluble form to the medium, ephrin-A5 induces growth their functions through a repellent mechanism, so that, for cone collapse, comparable to data from chick. example, an axon expressing an Eph receptor does not The analysis of growth cone behaviour in a gradient of invade a territory in which an ephrin is expressed. Eph soluble ephrin-A5 in the ‘turning assay’ revealed a receptor activation requires membrane-associated ligands. substratum-dependent reaction of Xenopus retinal axons. This feature discriminates ephrins from other molecules On fibronectin, we observed a repulsive response, with the sculpturing the nervous system such as netrins, slits and turning of growth cones away from higher concentrations class 3 semaphorins, which are secreted molecules. While of ephrin-A5. On laminin, retinal axons turned towards the ability of secreted molecules to guide axons, i.e.
    [Show full text]
  • Endothelin-2 Signaling in the Neural Retina Promotes the Endothelial Tip Cell State and Inhibits Angiogenesis
    Endothelin-2 signaling in the neural retina promotes PNAS PLUS the endothelial tip cell state and inhibits angiogenesis Amir Rattnera,1, Huimin Yua, John Williamsa,b, Philip M. Smallwooda,b, and Jeremy Nathansa,b,c,d,1 Departments of aMolecular Biology and Genetics, cNeuroscience, and dOphthalmology and bHoward Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Jeremy Nathans, August 20, 2013 (sent for review February 19, 2013) Endothelin signaling is required for neural crest migration and time lapse imaging studies of vascular development in zebrafish homeostatic regulation of blood pressure. Here, we report that and mammalian EC dynamics in explant culture show that the tip constitutive overexpression of Endothelin-2 (Edn2) in the mouse cell and stalk cell states are highly plastic, with frequent retina perturbs vascular development by inhibiting endothelial cell exchanges between the two cell states (8, 9). migration across the retinal surface and subsequent endothelial Several other signaling pathways are also essential for retinal cell invasion into the retina. Developing endothelial cells exist in vascular development. Norrin, a Muller-glia–derived ligand, and one of two states: tip cells at the growing front and stalk cells in its EC receptor Frizzled4 (Fz4), coreceptor Lrp5, and receptor the vascular plexus behind the front. This division of endothelial chaperone Tspan12 activate canonical Wnt signaling in de- cell states is one of the central organizing principles of angiogen- veloping ECs (10). In humans and mice, defects in any of these esis. In the developing retina, Edn2 overexpression leads to components lead to retinal hypovascularization.
    [Show full text]
  • Mir-146A Regulates Migration and Invasion by Targeting NRP2 in Circulating-Tumor Cell Mimicking Suspension Cells
    G C A T T A C G G C A T genes Article MiR-146a Regulates Migration and Invasion by Targeting NRP2 in Circulating-Tumor Cell Mimicking Suspension Cells Yeojin Do 1, Jin Gu Cho 1, Ji Young Park 1, Sumin Oh 1, Doyeon Park 1 , Kyung Hyun Yoo 1,2 , Myeong-Sok Lee 1,2, Byung Su Kwon 3,* , Jongmin Kim 1,2,* and Young Yang 2,* 1 Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; [email protected] (Y.D.); [email protected] (J.G.C.); [email protected] (J.Y.P.); [email protected] (S.O.); [email protected] (D.P.); [email protected] (K.H.Y.); [email protected] (M.-S.L.) 2 Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea 3 Department of Obstetrics and Gynecology, Kyung Hee University Medical Center, 23, Seoul 02447, Korea * Correspondence: [email protected] (B.S.K.); [email protected] (J.K.); [email protected] (Y.Y.); Tel.: +82-2-958-8837 (B.S.K.); +82-2-710-9553 (J.K.); +82-2-710-9590 (Y.Y.) Abstract: Cancer metastasis is the primary cause of cancer-related death and metastatic cancer has circulating-tumor cells (CTCs), which circulate in the bloodstream before invading other organs. Thus, understanding the precise role of CTCs may provide new insights into the metastasis process and reduce cancer mortality. However, the molecular characteristics of CTCs are not well understood due to a lack of number of CTCs.
    [Show full text]
  • 3B and Semaphorin-3F in Ovarian Cancer
    Published OnlineFirst February 2, 2010; DOI: 10.1158/1535-7163.MCT-09-0664 Research Article Molecular Cancer Therapeutics Hormonal Regulation and Distinct Functions of Semaphorin- 3B and Semaphorin-3F in Ovarian Cancer Doina Joseph1, Shuk-Mei Ho2, and Viqar Syed1 Abstract Semaphorins comprise a family of molecules that influence neuronal growth and guidance. Class-3 sema- phorins, semaphorin-3B (SEMA3B) and semaphorin-3F (SEMA3F), illustrate their effects by forming a com- plex with neuropilins (NP-1 or NP-2) and plexins. We examined the status and regulation of semaphorins and their receptors in human ovarian cancer cells. A significantly reduced expression of SEMA3B (83 kDa), SE- MA3F (90 kDa), and plexin-A3 was observed in ovarian cancer cell lines when compared with normal human ovarian surface epithelial cells. The expression of NP-1, NP-2, and plexin-A1 was not altered in human ovar- ian surface epithelial and ovarian cancer cells. The decreased expression of SEMA3B, SEMA3F, and plexin-A3 was confirmed in stage 3 ovarian tumors. The treatment of ovarian cancer cells with luteinizing hormone, follicle-stimulating hormone, and estrogen induced a significant upregulation of SEMA3B, whereas SEMA3F was upregulated only by estrogen. Cotreatment of cell lines with a hormone and its specific antagonist blocked the effect of the hormone. Ectopic expression of SEMA3B or SEMA3F reduced soft-agar colony for- mation, adhesion, and cell invasion of ovarian cancer cell cultures. Forced expression of SEMA3B, but not SEMA3F, inhibited viability of ovarian cancer cells. Overexpression of SEMA3B and SEMA3F reduced focal adhesion kinase phosphorylation and matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in ovarian cancer cells.
    [Show full text]
  • Semaphorin Signaling Guides Cranial Neural Crest Cell Migration in Zebrafish
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Biology 280 (2005) 373–385 www.elsevier.com/locate/ydbio Semaphorin signaling guides cranial neural crest cell migration in zebrafish Hung-Hsiang Yu, Cecilia B. Moens* Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Box 19024 Seattle, WA 98109, USA Received for publication 2 December 2004, revised 19 January 2005, accepted 28 January 2005 Abstract Cranial neural crest cells (NCCs) migrate into the pharyngeal arches in three primary streams separated by two cranial neural crest (NC)- free zones. Multiple tissues have been implicated in the guidance of cranial NCC migration; however, the signals provided by these tissues have remained elusive. We investigate the function of semaphorins (semas) and their receptors, neuropilins (nrps), in cranial NCC migration in zebrafish. We find that genes of the sema3F and sema3G class are expressed in the cranial NC-free zones, while nrp2a and nrp2b are expressed in the migrating NCCs. sema3F/3G expression is expanded homogeneously in the head periphery through which the cranial NCCs migrate in lzr/pbx4 mutants, in which the cranial NC streams are fused. Antisense morpholino knockdown of Sema3F/3G or Nrp2 suppresses the abnormal cranial NC phenotype of lzr/pbx4 mutants, demonstrating that aberrant Sema3F/3G-Nrp2 signaling is responsible for this phenotype and suggesting that repulsive Sema3F/3G-Npn2 signaling normally contributes to the guidance of migrating cranial NCCs. Furthermore, global over-expression of sema3Gb phenocopies the aberrant cranial NC phenotype of lzr/pbx4 mutants when endogenous Sema3 ligands are knocked down, consistent with a model in which the patterned expression of Sema3 ligands in the head periphery coordinates the migration of Nrp-expressing cranial NCCs.
    [Show full text]
  • 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
    [Show full text]
  • Hepatocyte Growth Factor: a Regulator of Inflammation and Autoimmunity
    Autoimmunity Reviews 14 (2015) 293–303 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Review Hepatocyte growth factor: A regulator of inflammation and autoimmunity Nicolas Molnarfi a,b,1, Mahdia Benkhoucha a,b,1, Hiroshi Funakoshi d, Toshikazu Nakamura e, Patrice H. Lalive a,b,c,⁎ a Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland b Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, University Hospital of Geneva, Geneva, Switzerland c Department of Genetics and Laboratory Medicine, Laboratory Medicine Service, University Hospital of Geneva, Geneva, Switzerland d Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa, Japan e Neurogen Inc., Nakahozumi, Ibaraki, Osaka, Japan article info abstract Article history: Hepatocyte growth factor (HGF) is a pleiotropic cytokine that has been extensively studied over several decades, Received 20 November 2014 but was only recently recognized as a key player in mediating protection of many types of inflammatory and au- Accepted 25 November 2014 toimmune diseases. HGF was reported to prevent and attenuate disease progression by influencing multiple Available online 1 December 2014 pathophysiological processes involved in inflammatory and immune response, including cell migration, matura- tion, cytokine production, antigen presentation, and T cell effector function. In this review, we discuss the actions Keywords: fl HGF and mechanisms of HGF in in ammation and immunity and the therapeutic potential of this factor for the treat- fl c-Met ment of in ammatory and autoimmune diseases. Inflammation © 2014 Elsevier B.V. All rights reserved. Autoimmunity Autoimmune regulator Therapy Contents 1.
    [Show full text]
  • 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts
    1,25-DIHYDROXYVITAMIN D3-INDUCED GENES IN OSTEOBLASTS: UNCOVERING NEW FUNCTIONS FOR MENINGIOMA 1 AND SEMAPHORIN 3B IN SKELETAL PHYSIOLOGY by XIAOXUE ZHANG Submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Thesis advisor: Paul N. MacDonald Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY May 2009 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. I dedicate this thesis to my mother and father for their lifelong love, encouragement and sacrifice TABLE OF CONTENTS Table of Contents ii List of Tables iii List of Figures iv Acknowledgements vii Abbreviations x Abstract xiii Chapter I Introduction 1 Chapter II Meningioma 1 (MN1) is a 1,25-dihydroxyvitamin D3- 44 induced transcription coactivator that promotes osteoblast proliferation, motility, differentiation, and function Chapter III Semaphorin 3B (SEMA3B) is a 1,25- 108 dihydroxyvitamin D3-induced gene in osteoblasts that promotes
    [Show full text]
  • Osteomalacia and Hyperparathyroid Bone Disease in Patients with Nephrotic Syndrome
    Osteomalacia and Hyperparathyroid Bone Disease in Patients with Nephrotic Syndrome Hartmut H. Malluche, … , David A. Goldstein, Shaul G. Massry J Clin Invest. 1979;63(3):494-500. https://doi.org/10.1172/JCI109327. Research Article Patients with nephrotic syndrome have low blood levels of 25 hydroxyvitamin D (25-OH-D) most probably because of losses in urine, and a vitamin D-deficient state may ensue. The biological consequences of this phenomenon on target organs of vitamin D are not known. This study evaluates one of these target organs, the bone. Because renal failure is associated with bone disease, we studied six patients with nephrotic syndrome and normal renal function. The glomerular filtration rate was 113±2.1 (SE) ml/min; serum albumin, 2.3±27 g/dl; and proteinuria ranged between 3.5 and 14.7 g/24 h. Blood levels of 25-OH-D, total and ionized calcium and carboxy-terminal fragment of immunoreactive parathyroid hormone were measured, and morphometric analysis of bone histology was made in iliac crest biopsies obtained after double tetracycline labeling. Blood 25-OH-D was low in all patients (3.2-5.1 ng/ml; normal, 21.8±2.3 ng/ml). Blood levels of both total (8.1±0.12 mg/dl) and ionized (3.8±0.21 mg/dl) calcium were lower than normal and three patients had true hypocalcemia. Blood immuno-reactive parathyroid hormone levels were elevated in all. Volumetric density of osteoid was significantly increased in three out of six patients and the fraction of mineralizing osteoid seams was decreased in all.
    [Show full text]
  • The Role of BMP Signaling in Osteoclast Regulation
    Journal of Developmental Biology Review The Role of BMP Signaling in Osteoclast Regulation Brian Heubel * and Anja Nohe * Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA * Correspondence: [email protected] (B.H.); [email protected] (A.N.) Abstract: The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP 2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP 2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP 2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP 2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established. Keywords: osteoclast; BMP; osteoporosis Citation: Heubel, B.; Nohe, A. The Role of BMP Signaling in Osteoclast Regulation.
    [Show full text]