DOCSLIB.ORG

Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption International Journal of Molecular Sciences Review Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption Hiroyuki Okada 1,2 , Koji Okabe 3 and Sakae Tanaka 1,* 1 Department of Orthopaedic Surgery, The University of Tokyo, Tokyo 113-8655, Japan; [email protected] 2 Center of Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan 3 Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-3-3815-5411 Abstract: Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via cal- cineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclasto- genesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca2+ storage. Ryanodine receptor, inositol trisphosphate receptor, 2+ and sarco/endoplasmic reticulum Ca ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca Citation: Okada, H.; Okabe, K.; oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains Tanaka, S. Finely-Tuned Calcium to be examined. Oscillations in Osteoclast Differentiation and Bone Resorption. Keywords: calcium oscillation; osteoclast; receptor activator of nuclear factor kappa B ligand Int. J. Mol. Sci. 2021, 22, 180. (RANKL); transient receptor potential (TRP) channel; costimulatory signal; immunoreceptor tyrosine- https://dx.doi.org/10.3390/ ijms22010180 based activation motif (ITAM) Received: 11 November 2020 Accepted: 23 December 2020 Published: 26 December 2020 1. Introduction Calcium (Ca2+) is a simple molecule, but has various cellular functions [1]. It acts as a Publisher’s Note: MDPI stays neu- common second messenger in many biological process [2,3]. For example, small changes tral with regard to jurisdictional claims in Ca2+ can induce dynamic cellular functions, including synapse transduction in neural in published maps and institutional cells [4], muscle contraction [5], and fertilization in oocytes [6]. affiliations. Hematopoietic stem cell-derived osteoclasts are electrically stable cells, and the Ca2+ concentrations in bone marrow macrophages (BMMs) and osteoclasts are maintained at almost constant levels. However, subtle changes in the Ca2+ levels with and without Copyright: © 2020 by the authors. Li- extracellular stimuli, so-called calcium oscillations (Ca oscillations), play important roles in censee MDPI, Basel, Switzerland. This the cellular differentiation, function, and death of osteoclasts. article is an open access article distributed The effect of Ca oscillations on the differentiation process of osteoclasts remains under under the terms and conditions of the debate. Receptor activator of nuclear factor kappa B ligand (RANKL) is an essential Creative Commons Attribution (CC BY) inducer of osteoclast differentiation [7]. Nuclear factor of activated T-cells 1 (NFATc1) is a license (https://creativecommons.org/ master regulator gene for osteoclastogenesis [8]. In addition to these essential factors for licenses/by/4.0/). Int. J. Mol. Sci. 2021, 22, 180. https://dx.doi.org/10.3390/ijms22010180 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 180 2 of 20 Int. J. Mol. Sci. 2021, 22, 180 2 of 19 a master regulator gene for osteoclastogenesis [8]. In addition to these essential factors for osteoclastogenesis,osteoclastogenesis, appropriat appropriatee Ca Ca oscillations oscillations are are necessar necessaryy depending depending on on the the situation situation forfor RANKL-inducedRANKL-induced NFATc1 auto-amplification.auto-amplification. InIn osteoclastosteoclast differentiation,differentiation, calcineurincalcineurin isis anan importantimportant activatoractivator ofof NFATc1NFATc1 converting convert- Caing oscillationsCa oscillations signals signals under under RANKL RANKL transduction transduction pathway pathway [[9].9]. Recent study study clarified clarified PICK1PICK1 is a positive regulator of calcineurin B B [10]. [10]. Another Another group group showed showed that that mTORC1 mTORC1 impedesimpedes NFATc1 activation by by calcineurin calcineurin [11]. [11]. Cyclosporine Cyclosporine A, A,which which is an is inhibitor an inhibitor of ofcalcineurin, calcineurin, inhibited inhibited bone bone resorption resorption by by os osteoclastteoclast in invitro vitro [12,13],[12,13 ],however, however, another another groupgroup reportedreported cyclosporinecyclosporine AA diddid notnot affectaffect bone bone resorption resorption significantly significantly [ 14[14].]. The The role role of calcineurinof calcineurin in bonein bone resorption resorption might might be be controversial. controversial. InIn this review, review, we we will will explain explain comprehensively comprehensively important important parts parts for forinducing inducing intra- in- tracellularcellular Ca Caoscillations oscillations (Figure (Figure 1). Initially,1). Initially, we will we willfocus focus on costimulatory on costimulatory signals signals of oste- of 2+ osteoclastogenesisoclastogenesis in the in upstream the upstream of Ca of oscillations. Ca oscillations. Next, Next, we will we willdiscuss discuss Ca2+ Cachannels,channels, es- especiallypecially transient transient receptor receptor potential potential (TRP) (TRP) channels. channels. Intracellular Intracellular storage storage also plays also an plays im- anportant important role in role fine-tuning in fine-tuning of Ca oscillation of Ca oscillations.s. Furthermore, Furthermore, environmental environmental factors around factors 2+ aroundosteoclasts osteoclasts affect intracellular affect intracellular Ca2+ concentration. Ca concentration. Finally,Finally, we will we present will present research research per- perspectivesspectives on Ca on Caoscillations oscillations in osteoclasts. in osteoclasts. FigureFigure 1.1. Schematic representation of the main modifiersmodifiers of calcium oscillations in osteoclasts. Some Some calcium channels, pumps, ITAM receptors, and intracellular organelles coordinate intracel- calcium channels, pumps, ITAM receptors, and intracellular organelles coordinate intracellular lular calcium oscillations in a proper manner. [Ca2+]i: intracellular calcium ion concentration; calcium oscillations in a proper manner. [Ca2+] : intracellular calcium ion concentration; RANK: RANK: receptor activator of nuclear factor kappai B; RANKL: RANK ligand; ITAM: immunorecep- receptortor tyrosine-based activator of activation nuclear factor motif; kappa FcRγ: B; Fc RANKL: receptor RANK gamma; ligand; DAP12: ITAM: DNAX-activating immunoreceptor protein tyrosine- of based12 kD; activation TRP: transient motif; receptor FcRγ: Fcpotential; receptor IP gamma;3: inositol DAP12: 1,4,5-trisphosphat DNAX-activatinge; RyR: proteinryanodine of 12receptor; kD; TRP: 2+ transientSERCA: sarco/endopl receptor potential;asmic reticulum IP3: inositol Ca ATPase. 1,4,5-trisphosphate; RyR: ryanodine receptor; SERCA: sarco/endoplasmic reticulum Ca2+ ATPase. 2. Costimulatory Signals during Osteoclast Development 2. Costimulatory Signals during Osteoclast Development Appropriate Ca oscillations are necessary for NFATc1 auto-amplification in osteo- Appropriate Ca oscillations are necessary for NFATc1 auto-amplification in osteoclas- clastogenesis [8]. Koga et al. reported that immunoreceptor tyrosine-based activation mo- togenesis [8]. Koga et al. reported that immunoreceptor tyrosine-based activation motif tif (ITAM)-harboring adaptors transduced costimulatory signals during osteoclastogene- (ITAM)-harboring adaptors transduced costimulatory signals during osteoclastogenesis. sis. ITAM receptor-adaptor complexes acted as key modulators of Ca oscillations in ITAM receptor-adaptor complexes acted as key modulators of Ca oscillations in BMMs [15]. BMMs [15]. Phosphorylated ITAM adaptor proteins recruit Syk tyrosine kinase and in- Phosphorylated ITAM adaptor proteins recruit Syk tyrosine kinase and induce Ca oscil- duce Ca oscillations through activation of PLCγ [16]. Syk, c-Src, and αvβ3 integrin coop- lations through activation of PLCγ [16]. Syk, c-Src, and αvβ3 integrin cooperate under erate under costimulatory signaling [17]. Protein tyrosine kinase inhibitors disrupt actin costimulatory signaling [17]. Protein tyrosine kinase inhibitors disrupt actin organization organization and osteoclast activity [18]. and osteoclast activity [18].
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]
  • Potassium Channels in Epilepsy
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Potassium Channels in Epilepsy Ru¨diger Ko¨hling and Jakob Wolfart Oscar Langendorff Institute of Physiology, University of Rostock, Rostock 18057, Germany Correspondence: [email protected] This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dy- namic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With 80 potassium channel types, of which 10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models. INTRODUCTION TO POTASSIUM evolutionary appearance of voltage-gated so- CHANNELS dium (Nav)andcalcium (Cav)channels, Kchan- nels are further diversified in relation to their otassium (K) channels are related to epilepsy newer function, namely, keeping neuronal exci- Psyndromes on many different levels, ranging tation within limits (Anderson and Greenberg from direct control of neuronal excitability and 2001; Hille 2001).
    [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]
  • Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer
    UCSF UC San Francisco Previously Published Works Title Expression profiling of ion channel genes predicts clinical outcome in breast cancer Permalink https://escholarship.org/uc/item/1zq9j4nw Journal Molecular Cancer, 12(1) ISSN 1476-4598 Authors Ko, Jae-Hong Ko, Eun A Gu, Wanjun et al. Publication Date 2013-09-22 DOI http://dx.doi.org/10.1186/1476-4598-12-106 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ko et al. Molecular Cancer 2013, 12:106 http://www.molecular-cancer.com/content/12/1/106 RESEARCH Open Access Expression profiling of ion channel genes predicts clinical outcome in breast cancer Jae-Hong Ko1, Eun A Ko2, Wanjun Gu3, Inja Lim1, Hyoweon Bang1* and Tong Zhou4,5* Abstract Background: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. Methods: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test.
    [Show full text]
  • Ion Channels 3 1
    r r r Cell Signalling Biology Michael J. Berridge Module 3 Ion Channels 3 1 Module 3 Ion Channels Synopsis Ion channels have two main signalling functions: either they can generate second messengers or they can function as effectors by responding to such messengers. Their role in signal generation is mainly centred on the Ca2 + signalling pathway, which has a large number of Ca2+ entry channels and internal Ca2+ release channels, both of which contribute to the generation of Ca2 + signals. Ion channels are also important effectors in that they mediate the action of different intracellular signalling pathways. There are a large number of K+ channels and many of these function in different + aspects of cell signalling. The voltage-dependent K (KV) channels regulate membrane potential and + excitability. The inward rectifier K (Kir) channel family has a number of important groups of channels + + such as the G protein-gated inward rectifier K (GIRK) channels and the ATP-sensitive K (KATP) + + channels. The two-pore domain K (K2P) channels are responsible for the large background K current. Some of the actions of Ca2 + are carried out by Ca2+-sensitive K+ channels and Ca2+-sensitive Cl − channels. The latter are members of a large group of chloride channels and transporters with multiple functions. There is a large family of ATP-binding cassette (ABC) transporters some of which have a signalling role in that they extrude signalling components from the cell. One of the ABC transporters is the cystic − − fibrosis transmembrane conductance regulator (CFTR) that conducts anions (Cl and HCO3 )and contributes to the osmotic gradient for the parallel flow of water in various transporting epithelia.
    [Show full text]
  • Spatial Distribution of Leading Pacemaker Sites in the Normal, Intact Rat Sinoa
    Supplementary Material Supplementary Figure 1: Spatial distribution of leading pacemaker sites in the normal, intact rat sinoatrial 5 nodes (SAN) plotted along a normalized y-axis between the superior vena cava (SVC) and inferior vena 6 cava (IVC) and a scaled x-axis in millimeters (n = 8). Colors correspond to treatment condition (black: 7 baseline, blue: 100 µM Acetylcholine (ACh), red: 500 nM Isoproterenol (ISO)). 1 Supplementary Figure 2: Spatial distribution of leading pacemaker sites before and after surgical 3 separation of the rat SAN (n = 5). Top: Intact SAN preparations with leading pacemaker sites plotted during 4 baseline conditions. Bottom: Surgically cut SAN preparations with leading pacemaker sites plotted during 5 baseline conditions (black) and exposure to pharmacological stimulation (blue: 100 µM ACh, red: 500 nM 6 ISO). 2 a &DUGLDFIoQChDQQHOV .FQM FOXVWHU &DFQDG &DFQDK *MD &DFQJ .FQLS .FQG .FQK .FQM &DFQDF &DFQE .FQM í $WSD .FQD .FQM í .FQN &DVT 5\U .FQM &DFQJ &DFQDG ,WSU 6FQD &DFQDG .FQQ &DFQDJ &DFQDG .FQD .FQT 6FQD 3OQ 6FQD +FQ *MD ,WSU 6FQE +FQ *MG .FQN .FQQ .FQN .FQD .FQE .FQQ +FQ &DFQDD &DFQE &DOP .FQM .FQD .FQN .FQG .FQN &DOP 6FQD .FQD 6FQE 6FQD 6FQD ,WSU +FQ 6FQD 5\U 6FQD 6FQE 6FQD .FQQ .FQH 6FQD &DFQE 6FQE .FQM FOXVWHU V6$1 L6$1 5$ /$ 3 b &DUGLDFReFHSWRUV $GUDF FOXVWHU $GUDD &DY &KUQE &KUP &KJD 0\O 3GHG &KUQD $GUE $GUDG &KUQE 5JV í 9LS $GUDE 7SP í 5JV 7QQF 3GHE 0\K $GUE *QDL $QN $GUDD $QN $QN &KUP $GUDE $NDS $WSE 5DPS &KUP 0\O &KUQD 6UF &KUQH $GUE &KUQD FOXVWHU V6$1 L6$1 5$ /$ 4 c 1HXURQDOPURWHLQV
    [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]
  • 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]
  • Distinct Expression/Function of Potassium and Chloride Channels Contributes to the Diverse Volume Regulation in Cortical Astrocytes of GFAP/EGFP Mice
    Distinct Expression/Function of Potassium and Chloride Channels Contributes to the Diverse Volume Regulation in Cortical Astrocytes of GFAP/EGFP Mice Jana Benesova1,3, Vendula Rusnakova2, Pavel Honsa1,3, Helena Pivonkova1,3, David Dzamba1,3, Mikael Kubista2,4, Miroslava Anderova1* 1 Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic, 2 Laboratory of Gene Expression, Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic, 3 Second Medical Faculty, Charles University, Prague, Czech Republic, 4 TATAA Biocenter, Gothenburg, Sweden Abstract Recently, we have identified two astrocytic subpopulations in the cortex of GFAP-EGFP mice, in which the astrocytes are visualized by the enhanced green–fluorescent protein (EGFP) under the control of the human glial fibrillary acidic protein (GFAP) promotor. These astrocytic subpopulations, termed high response- (HR-) and low response- (LR-) astrocytes, differed in the extent of their swelling during oxygen-glucose deprivation (OGD). In the present study we focused on identifying the ion channels or transporters that might underlie the different capabilities of these two astrocytic subpopulations to regulate their volume during OGD. Using three-dimensional confocal morphometry, which enables quantification of the total astrocytic volume, the effects of selected inhibitors of K+ and Cl2 channels/transporters or glutamate transporters on astrocyte volume changes were determined during 20 minute-OGD in situ. The inhibition of volume regulated anion channels (VRACs) and two-pore domain potassium channels (K2P) highlighted their distinct contributions to volume regulation in HR-/LR-astrocytes. While the inhibition of VRACs or K2P channels revealed their contribution to the swelling of HR-astrocytes, in LR-astrocytes they were both involved in anion/K+ effluxes.
    [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]
  • The Products of Bone Resorption and Their Roles in Metabolism: Lessons from the Study of Burns
    Concept Paper The Products of Bone Resorption and Their Roles in Metabolism: Lessons from the Study of Burns Gordon L. Klein Department of Orthopaedic Surgery and Rehabilitation, University of Texas Medical Branch, Galveston, TX 77555-0165, USA; [email protected] Abstract: Surprisingly little is known about the factors released from bone during resorption and the metabolic roles they play. This paper describes what we have learned about factors released from bone, mainly through the study of burn injuries, and what roles they play in post-burn metabolism. From these studies, we know that calcium, phosphorus, and magnesium, along with transforming growth factor (TGF)-β, are released from bone following resorption. Additionally, studies in mice from Karsenty’s laboratory have indicated that undercarboxylated osteocalcin is also released from bone during resorption. Questions arising from these observations are discussed as well as a variety of potential conditions in which release of these factors could play a significant role in the pathophysiology of the conditions. Therapeutic implications of understanding the metabolic roles of these and as yet other unidentified factors are also raised. While much remains unknown, that which has been observed provides a glimpse of the potential importance of this area of study. Keywords: bone resorption; calcium; phosphorus; TGF-β; undercarboxylated osteocalcin Citation: Klein, G.L. The Products of Bone Resorption and Their Roles in 1. Introduction Metabolism: Lessons from the Study of Burns. Osteology 2021, 1, 73–79. In recent years we have learned much about the mechanisms of bone formation and https://doi.org/10.3390/ resorption, the cells involved, and many of the factors that affect and link the two processes.
    [Show full text]
  • Hormone Resulting in Stimulation of Bone Resorption Edward M
    Adenyl Cyclase and Interleukin 6 Are Downstream Effectors of Parathyroid Hormone Resulting in Stimulation of Bone Resorption Edward M. Greenfield, Steven M. Shaw, Sandra A. Gomik, and Michael A. Banks Department of Orthopaedics and Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-5000 Abstract * osteoclast * cytokine * cell-cell interactions * bone resorp- tion Parathyroid hormone and other bone resorptive agents function, at least in part, by inducing osteoblasts to secrete Introduction cytokines that stimulate both differentiation and resorptive activity of osteoclasts. We previously identified two poten- Net bone loss, in conditions such as osteoporosis, results from tially important cytokines by demonstrating that parathy- a disturbance in the normal balance between bone resorption roid hormone induces expression by osteoblasts of 1L-6 and by osteoclasts and bone formation by osteoblasts. Thus, knowl- leukemia inhibitory factor without affecting levels of 14 edge of the mechanisms that regulate both resorption and forma- other cytokines. Although parathyroid hormone activates tion of bone is fundamental to the understanding of the patho- multiple signal transduction pathways, induction of IL-6 genesis of these diseases. and leukemia inhibitory factor is dependent on activation In addition to forming bone, osteoblasts regulate osteoclast of adenyl cyclase. This study demonstrates that adenyl cy- resorptive activity in response to parathyroid hormone (PTH) clase is also required for stimulation of osteoclast activity and other resorptive agents (1, 2). This concept is best sup- in cultures containing osteoclasts from rat long bones and ported by evidence that many agents, including PTH, only stim- UMR106-01 rat osteoblast-like osteosarcoma cells. Since ulate osteoclast resorptive activity in the presence of osteoblasts the stimulation by parathyroid hormone of both cytokine or conditioned media from osteoblasts that had been exposed production and bone resorption depends on the same signal to PTH (3, 4).
    [Show full text]