DOCSLIB.ORG

Circulating Sclerostin in Disorders of Parathyroid Gland Function

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Circulating Sclerostin in Disorders of Parathyroid Gland Function ORIGINAL ARTICLE Endocrine Research Circulating Sclerostin in Disorders of Parathyroid Gland Function Aline G. Costa, Serge Cremers, Mishaela R. Rubin, Donald J. McMahon, James Sliney, Jr., Marise Lazaretti-Castro, Shonni J. Silverberg, and John P. Bilezikian Department of Medicine (A.G.C., S.C., M.R.R., D.J.M., J.S., S.J.S., J.P.B.), Division of Endocrinology, Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University, New York, New Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 York 10032; and Department of Medicine (A.G.C., M.L.-C.), Division of Endocrinology, Sa˜ o Paulo Federal University, Sa˜ o Paulo 04044, Brazil Context: Sclerostin, a protein encoded by the SOST gene in osteocytes and an antagonist of the Wnt signaling pathway, is down-regulated by PTH administration. Disorders of parathyroid function are useful clinical settings to study this relationship. Objective: The objective of the study was to evaluate sclerostin in two different disorders of parathyroid function, primary hyperparathyroidism and hypoparathyroidism, and to analyze the relationship between sclerostin and PTH, bone markers, and bone mineral density. Design: This is a cross-sectional study. Setting: The study was conducted at a clinical research center. Patients: Twenty hypoparathyroid and 20 hyperparathyroid patients were studied and compared to a reference control group. Results: Serum sclerostin was significantly higher in hypoparathyroid subjects than in hyperparathy- roid subjects (P Ͻ 0.0001) and controls (P Ͻ 0.0001). PTH was negatively associated with sclerostin, achieving statistical significance in hypoparathyroidism (r ϭϪ0.545; P ϭ 0.02). The bone turnover markers, cross-linked C-telopeptide of type I collagen (CTX) and amino-terminal propeptide of type I collagen (P1NP), were differently associated with sclerostin according to the parathyroid disorder. In primary hyperparathyroidism, bone turnover markers were associated negatively with sclerostin (for P1NP, r ϭϪ0.490; P ϭ 0.03). In hypoparathyroidism, bone turnover markers were associated positively with sclerostin (for CTX, r ϭϩ0.571; P ϭ 0.01). Although there was no significant correlation between bone mineral density and sclerostin in either parathyroid disorder, there was a significant positive relationship between sclerostin and bone mineral content in hypoparathyroidism. Conclusions: The results are consistent with the hypothesis that PTH is a regulator of sclerostin in human disorders of parathyroid function. In addition, the results suggest that bone mineral content may be another factor that influences sclerostin. (J Clin Endocrinol Metab 96: 3804–3810, 2011) clerostin is a secretory product of the osteocyte, the mental influences, the osteocyte signals the two other key S most abundant cell in the skeleton (1, 2). Long con- bone cells, the osteoblast and the osteoclast, by producing sidered to be an outdated osteoblast, inactive and “en- molecules such as sclerostin (3–5). tombed” in the mineralized matrix of bone, the osteocyte Sclerostin, a glycoprotein encoded by the osteocyte is now acknowledged to be a master skeletal signaling cell. SOST gene, regulates the activities of the mature osteo- Responding to mechanical stress and to other environ- blast as well as the osteoblast lineage pathway. Inactivat- ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BAP, Bone-specific alkaline phosphatase; BMC, bone mineral content; BMD, Printed in U.S.A. bone mineral density; CTX, cross-linked C-telopeptide of type I collagen; DXA, dual-energy Copyright © 2011 by The Endocrine Society x-ray absorptiometry; FN, femoral neck; HypoPT, hypoparathyroidism; LS, lumbar spine; 25- doi: 10.1210/jc.2011-0566 Received March 3, 2011. Accepted August 29, 2011. OHD, 25-hydroxyvitamin D; PHPT, primary hyperparathyroidism; P1NP, serum amino-terminal First Published Online September 20, 2011 propeptide of type I collagen; 1/3 radius, one third distal radius; TH, total hip. 3804 jcem.endojournals.org J Clin Endocrinol Metab, December 2011, 96(12):3804–3810 J Clin Endocrinol Metab, December 2011, 96(12):3804–3810 jcem.endojournals.org 3805 ing mutations of the SOST gene lead to exuberant bone Serum measurements growth, as demonstrated in the human disorders scleros- Blood samples were prepared, and sera were immediately Ϫ teosis and van Buchem’s disease (6–9). Affected individ- frozen at 70 C. Serum sclerostin levels were measured using an ELISA developed by TECOmedical Group. This ELISA uses a uals have exceedingly dense bones as assessed by radio- biotinylated polyclonal antibody as well as a horseradish per- graphic and dual-energy x-ray absorptiometry (DXA) oxidase-labeled secondary monoclonal antibody that specifi- measurements, but they are of normal quality, and frac- cally recognizes human sclerostin. The detection limit of the as- tures have not been reported. A phenotype similar to say is 0.15 ng/ml. No study subjects demonstrated sclerostin sclerosteosis is seen in a mouse Sost knockout model (10). levels below this detection limit. Intra- and interassay precision Sclerostin’s control of osteoblast action and develop- are 1.6 and 2.7%, respectively. Results for the sclerostin mea- surements are reported throughout in nanograms per milliliter ment is mediated by the anabolic Wnt and BMP signaling (multiply by 44 to convert to picomoles per liter). Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 pathways. By binding to the LRP5/LRP6 receptor com- PTH was measured in duplicate using the immunoradiomet- plex, sclerostin inhibits the activity of molecules such as ric assay for the quantitative determination of human total intact the Wnt pathway’s ␤-catenin, a major activator of ana- PTH as developed by Scantibodies Laboratories, Inc. (Santee, bolic genes in the nucleus of the osteoblast (2, 11–14). CA). Normal range is 14–66 pg/ml. Interassay precision is 8.4%, and the intraassay precision is 5.7%. Serum amino-terminal pro- Sclerostin also has been shown to inhibit BMP7 secretion peptide of type I collagen (P1NP), cross-linked C-telopeptide of by osteocytes in mice (15). type I collagen (CTX), and 25-hydroxyvitamin D (25-OHD) PTH has increasingly been implicated as one of the were measured simultaneously by immunochemiluminescence factors involved in the regulation of sclerostin (16). Evi- assays on the IDS-iSYS Multi-Discipline automated analyzer dence that PTH regulates sclerostin expression comes (Immunodiagnostics Systems, Scottsdale, AZ). Normal range for P1NP is 27.7–127.6 ng/ml. Sensitivity is below 1 ng/ml, and from human and animal studies at both the cellular and intra- and interassay precision are below 4% and below 6%, molecular level (17–20). Diseases characterized by exces- respectively. Dynamic range for CTX is 0.033–6.000 ng/ml, and sive or deficient PTH provide a useful model to further intra- and interassay precision is 4.9 and 8.8%, respectively. explore the relationship between PTH and sclerostin. In Normal reference values for 25-OHD are set at above 30 ng/ml, this study, we measured circulating sclerostin levels in pa- with sensitivity of 5.5 ng/ml and intra- and interassay precision tients with overproduction or deficient PTH, namely pri- of below 8% and below 10%, respectively. mary hyperparathyroidism (PHPT) or hypoparathyroid- Bone mineral density (BMD) ism (HypoPT). BMD was measured at the lumbar spine (LS; L1–L4), total hip (TH), femoral neck (FN), and distal one-third radius (1/3 radius) by DXA (Hologic 4500W; Hologic Inc., Bedford, MA). The Subjects and Methods short-term in vivo precision error (root-mean-square SD) was 0.026 g/cm2 for L1–L4, 0.032 g/cm2 for the TH, 0.041 g/cm2 for Subjects the FN, and 0.033 g/cm2 for the forearm. Serum samples were obtained from ongoing HypoPT and PHPT studies at the Metabolic Bone Diseases Unit of Columbia Statistical analysis University Medical Center. A convenience sample consisting Results are expressed as mean Ϯ SEM. Serum chemistry mea- of 20 subjects (10 postmenopausal women and 10 men) with sures were log-transformed before analysis, and tests were ad- HypoPT and 20 subjects (10 postmenopausal women and 10 justed for age and unequal variances when appropriate. HypoPT men) with PHPT was chosen. HypoPT was defined as chronic and PHPT groups were evaluated by two-sided independent t- hypocalcemia in association with levels of PTH below the PTH tests. Each clinical group was compared with controls by inde- assay reference range (Ͻ10 pg/ml). PHPT was defined by hyper- pendent t-test also. Pearson correlations were used to assess the calcemia in association with levels of PTH in the upper range or association between sclerostin and bone mineral indices. Linear above the PTH assay reference range (Ͼ65 pg/ml). Exclusion regression was used to fit a least squares prediction line between criteria included: liver or kidney disease, Paget’s disease, rheu- sclerostin (log10) and CTX (log10) and P1NP (log10) separately matoid arthritis, diabetes mellitus, Cushing’s syndrome, multi- for each group. A value of P Ͻ 0.05 was considered significant. ple myeloma or any other malignancy, current treatment with Statistical analysis was performed using SAS, version 9.2 (SAS any bisphosphonate, glucocorticoids, calcitonin, raloxifene, es- Institute, Inc., Cary, NC). trogens, fluoride, lithium, or methotrexate. Serum was obtained, and DXA measurements were made before any patient under- went pharmacological (PTH for HypoPT) or surgical (parathy- Results roidectomy for PHPT) treatment for their disease. Sclerostin se- rum of 31 healthy subjects (15 men and 16 postmenopausal Baseline biochemical and DXA data women; age range, 37 to 79 yr) were used as the control group Demographic data are shown in Table 1. HypoPT and (provided by TECOmedical AG, Sissach, Switzerland). The study was approved by the Institutional Review Board of Co- PHPT subjects were of similar age and body mass index.
Load more

Recommended publications
  • Supplemental Information to Mammadova-Bach Et Al., “Laminin Α1 Orchestrates VEGFA Functions in the Ecosystem of Colorectal Carcinogenesis”
    Supplemental information to Mammadova-Bach et al., “Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinogenesis” Supplemental material and methods Cloning of the villin-LMα1 vector The plasmid pBS-villin-promoter containing the 3.5 Kb of the murine villin promoter, the first non coding exon, 5.5 kb of the first intron and 15 nucleotides of the second villin exon, was generated by S. Robine (Institut Curie, Paris, France). The EcoRI site in the multi cloning site was destroyed by fill in ligation with T4 polymerase according to the manufacturer`s instructions (New England Biolabs, Ozyme, Saint Quentin en Yvelines, France). Site directed mutagenesis (GeneEditor in vitro Site-Directed Mutagenesis system, Promega, Charbonnières-les-Bains, France) was then used to introduce a BsiWI site before the start codon of the villin coding sequence using the 5’ phosphorylated primer: 5’CCTTCTCCTCTAGGCTCGCGTACGATGACGTCGGACTTGCGG3’. A double strand annealed oligonucleotide, 5’GGCCGGACGCGTGAATTCGTCGACGC3’ and 5’GGCCGCGTCGACGAATTCACGC GTCC3’ containing restriction site for MluI, EcoRI and SalI were inserted in the NotI site (present in the multi cloning site), generating the plasmid pBS-villin-promoter-MES. The SV40 polyA region of the pEGFP plasmid (Clontech, Ozyme, Saint Quentin Yvelines, France) was amplified by PCR using primers 5’GGCGCCTCTAGATCATAATCAGCCATA3’ and 5’GGCGCCCTTAAGATACATTGATGAGTT3’ before subcloning into the pGEMTeasy vector (Promega, Charbonnières-les-Bains, France). After EcoRI digestion, the SV40 polyA fragment was purified with the NucleoSpin Extract II kit (Machery-Nagel, Hoerdt, France) and then subcloned into the EcoRI site of the plasmid pBS-villin-promoter-MES. Site directed mutagenesis was used to introduce a BsiWI site (5’ phosphorylated AGCGCAGGGAGCGGCGGCCGTACGATGCGCGGCAGCGGCACG3’) before the initiation codon and a MluI site (5’ phosphorylated 1 CCCGGGCCTGAGCCCTAAACGCGTGCCAGCCTCTGCCCTTGG3’) after the stop codon in the full length cDNA coding for the mouse LMα1 in the pCIS vector (kindly provided by P.
    [Show full text]
  • Gingival Crevicular Fluid Levels of Sclerostin, Osteoprotegerin, And
    Volume 86 • Number 12 Gingival Crevicular Fluid Levels of Sclerostin, Osteoprotegerin, and Receptor Activator of Nuclear Factor-kB Ligand in Periodontitis Umut Balli,* Ahmet Aydogdu,† Figen Ongoz Dede,* Cigdem Coskun Turer,* and Berrak Guven‡ Background: To investigate changes in the levels and rel- ative ratios of sclerostin, osteoprotegerin (OPG), and recep- tor activator of nuclear factor-kB ligand (RANKL) in the gingival crevicular fluid (GCF) of patients with periodontitis after non-surgical periodontal treatment. Methods: Fifty-four individuals (27 healthy controls and 27 patients with chronic periodontitis [CP]) were enrolled in eriodontal disease is a complex the study. Periodontitis patients received non-surgical peri- biologic process related to the in- odontal therapy. GCF sampling and clinical periodontal pa- Pteraction between groups of mi- rameters were assessed before and 6 weeks after therapy. croorganisms and the host immune/ Sclerostin, OPG, and RANKL levels were measured by enzyme- inflammatory response.1 When the bal- linked immunosorbent assay, and their relative ratios were ance between microbial challenge and calculated. host response is disturbed, periodontal Results: Total amounts and concentrations of sclerostin breakdown (clinical attachment loss [AL] were significantly higher in patients with CP than in healthy and alveolar bone resorption) can oc- individuals (P <0.025) and decreased after treatment cur.1,2 Microorganisms and their prod- (P <0.05). The RANKL/OPG ratio was significantly lower in ucts are the primary etiologic factors that healthy individuals than in patients with periodontitis before directly initiate periodontal disease. and after treatment (P <0.025), but no significant difference However, the majority of periodontal was observed in patients with periodontitis after treatment breakdown is caused by endogenous (P >0.05).
    [Show full text]
  • Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/ LRP6 Signaling
    Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/ LRP6 Signaling Maarten van Dinther1, Juan Zhang1, Stella E. Weidauer2, Verena Boschert2, Eva-Maria Muth2, Achim Knappik3, David J. J. de Gorter1, Puck B. van Kasteren1¤, Christian Frisch3, Thomas D. Mueller2, Peter ten Dijke1* 1 Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands, 2 Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs Institut, Wuerzburg, Germany, 3 AbD Serotec, a Bio-Rad company, Puchheim, Germany Abstract Sclerosteosis is a rare high bone mass disease that is caused by inactivating mutations in the SOST gene. Its gene product, Sclerostin, is a key negative regulator of bone formation and might therefore serve as a target for the anabolic treatment of osteoporosis. The exact molecular mechanism by which Sclerostin exerts its antagonistic effects on Wnt signaling in bone forming osteoblasts remains unclear. Here we show that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6. Unlike Dickkopf1 (DKK1), Sclerostin does not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with [125I]Sclerostin identified LRP6 as the main specific Sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with Sclerostin fused to recombinant green fluorescent protein (GFP) this was internalized, likely via a Clathrin-dependent process, and subsequently degraded in a temperature and proteasome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of Sclerostin- GFP, which was reduced by the addition of an excess of non-GFP-fused Sclerostin.
    [Show full text]
  • Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [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]
  • Regulation of Osteoblast Differentiation by Micrornas
    MQP-BIO-DSA-7214 REGULATION OF OSTEOBLAST DIFFERENTIATION BY MICRORNAS A Major Qualifying Project Report Submitted to the Faculty of the WORCESTER POLYTECHNIC INSTITUTE in partial fulfillment of the requirements for the Degree of Bachelor of Science in Biology and Biotechnology by _________________________ Mohammad Jafferji April 30, 2009 APPROVED: _________________________ _________________________ Jane Lian, Ph.D. David Adams, Ph.D. Cell Biology Biology and Biotechnology Umass Medical Center WPI Project Advisor Major Advisor i ABSTRACT MicroRNAs (miRs) are non-coding ~22 nucleotide RNAs which attenuate protein levels in the cell and have been shown to be important in regulating mammalian embryo development, tissue morphogenesis, cell growth, and differentiation. Very few studies have examined miRs during bone formation in vivo or during development of the osteoblast phenotype. Osteoblasts produce bone tissue matrix, secreting many proteins that support tissue mineralization. Here we identified and functionally characterized several microRNAs expressed during 3 stages of osteoblast differentiation: undifferentiated, osteoprogenitor, and most differentiated. Our results show that many miRs are gradually upregulated from growth to mineralization, with a more significant increase at the mineralization stage. Database analysis revealed that these miRs target well established pathways for bone formation including Wnt, BMP and MAPK pathways, which must be tightly regulated for normal osteoblast growth and differentiation. Our studies then focused on one representative microRNA, miR-218, which we found directly targets transducer of ERB1 (TOB1) and sclerostin (SOST) (both are negative inhibitors of Wnt signaling) as shown by 3’UTR luciferase reporter assays of each target. This approach demonstrates that miR-218 binds to the complementary 3’ UTR sequence in each target to decrease reporter activity, providing evidence for miR-218 regulation of TOB1 and SOST.
    [Show full text]
  • Sclerostin in Oral Tissues: Distribution, Biological Functions and Potential Therapeutic Role
    Review Article Open Access Journal of Review Article Biomedical Science ISSN: 2690-487X Sclerostin in Oral Tissues: Distribution, Biological Functions and Potential Therapeutic Role Fangyuan Shuai1, Aileen To2, Yan Jing3 and Xianglong Han1* 1State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, China 2Texas A&M College of Dentistry, D3 dental student, USA 3Texas A&M College of Dentistry, Department of Orthodontics, USA ABSTRACT Sclerostin is a well-known osteogenic negative regulator whose biological functions have been widely studied in bone homeostasis. Targeting sclerostin via monoclonal antibodies was shown to be a powerful strategy for bone-related diseases. Traditionally, to osteocytes, there are other cell types in oral tissues that can produce sclerostin. Sclerostin regulates the formation of dental andsclerostin periodontal was known structures as an and osteocyte-specific is also involved inglycoprotein. various physiological However, andin recent pathological studies, events it has in been oral showntissues. thatThus, in sclerostin addition modulation has been determined as a possible treatment strategy for periodontium-related diseases. To develop the therapeutic oral tissues. In this review, we highlight the existing awareness of sclerostin’s functions in oral tissues; the roles it plays in dental and periodontalpotential of sclerostindiseases and and treatments; its antibodies and in the the therapeutic field of dentistry, potential researchers of sclerostin must and clearly its antibodies
    [Show full text]
  • Sostdc1 Regulates NK Cell Maturation and Cytotoxicity
    Published February 27, 2019, doi:10.4049/jimmunol.1801157 The Journal of Immunology Sostdc1 Regulates NK Cell Maturation and Cytotoxicity Alberto J. Millan,* Sonny R. Elizaldi,* Eric M. Lee,* Jeffrey O. Aceves,* Deepa Murugesh,* Gabriela G. Loots,*,† and Jennifer O. Manilay* NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain–containing-1 (Sostdc1)inNK cell development and function. Sostdc1-knockout (Sostdc12/2) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27+CD11b+) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc12/2 mice is also changed. Lower frequencies of Sostdc12/2 splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+,G2+,H+, and D+ populations were universally decreased at the most mature (CD272CD11b+) stage. We hypothesized that the Ly49 repertoire in Sostdc12/2 mice would correlate with NK killing ability and observed that Sostdc12/2 NK cells are hyporesponsive against MHC class I–deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-g expression to controls. Consistent with Sostdc1’s known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc12/2 NK cells. Expression of the NK development gene Id2 was decreased in Sostdc12/2 immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources.
    [Show full text]
  • The Effect of Parathyroid Hormone on Osteogenesis Is Mediated Partly by Osteolectin Downloaded by Guest on September 28, 2021 INAUGURAL ARTICLE CELL BIOLOGY
    The effect of parathyroid hormone on osteogenesis is INAUGURAL ARTICLE mediated partly by osteolectin Jingzhu Zhanga, Adi Cohenb, Bo Shena, Liming Dua, Alpaslan Tasdogana, Zhiyu Zhaoa, Elizabeth J. Shaneb, and Sean J. Morrisona,c,d,1 aChildren’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75235; bDepartment of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032; cHHMI, University of Texas Southwestern Medical Center, Dallas, TX 75235; and dDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75235 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2020. Contributed by Sean J. Morrison, April 16, 2021 (sent for review December 19, 2020; reviewed by Hank Kronenberg, Noriaki Ono, and Joy Y. Wu) We previously described a new osteogenic growth factor, osteo- use (14). Existing therapies include antiresorptive agents that slow lectin/Clec11a, which is required for the maintenance of skeletal bone loss, such as bisphosphonates (15, 16) and estrogens (17), bone mass during adulthood. Osteolectin binds to Integrin α11 and anabolic agents that increase bone formation, such as para- (Itga11), promoting Wnt pathway activation and osteogenic dif- thyroid hormone (PTH) (18), PTH-related protein (19), and ferentiation by leptin receptor+ (LepR+) stromal cells in the bone sclerostin inhibitor (SOSTi) (20). While these therapies increase marrow. Parathyroid hormone (PTH) and sclerostin inhibitor bone mass and reduce fracture risk, they are not a cure. (SOSTi) are bone anabolic agents that are administered to patients PTH promotes both anabolic and catabolic bone remodeling with osteoporosis.
    [Show full text]
  • Role and Mechanism of Action of Sclerostin in Bone
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE HHS Public Access provided by IUPUIScholarWorks Author manuscript Author ManuscriptAuthor Manuscript Author Bone. Author Manuscript Author manuscript; Manuscript Author available in PMC 2018 March 01. Published in final edited form as: Bone. 2017 March ; 96: 29–37. doi:10.1016/j.bone.2016.10.007. Role and mechanism of action of Sclerostin in bone Jesus Delgado-Calle1,3, Amy Y. Sato1, and Teresita Bellido1,2,3,* 1Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 2Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana 3Roudebush Veterans Administration Medical Center, Indianapolis, Indiana Abstract After discovering that lack of Sost/sclerostin expression is the cause of the high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive animal experimentation and clinical studies demonstrated that sclerostin plays a critical role in bone homeostasis and that its deficiency or pharmacological neutralization increases bone formation. Dysregulation of sclerostin expression also underlies the pathophysiology of skeletal disorders characterized by loss of bone mass as well as the damaging effects of some cancers in bone. Thus, sclerostin has quickly become a promising molecular target for the treatment of osteoporosis and other skeletal diseases, and beneficial skeletal outcomes are observed in animal studies and clinical trials using neutralizing
    [Show full text]
  • Synthesis, Gene Regulation and Osteoblast Differentiation
    Curr. Issues Mol. Biol. 15: 7-18. Online journal at http://www.cimb.orgMicroRNAs 7 MicroRNAs: Synthesis, Gene Regulation and Osteoblast Differentiation S. Vimalraj and N. Selvamurugan* tissue. They have the potential to undergo multilineage differentiation, such as osteoblasts, chondrocytes, Department of Biotechnology, School of Bioengineering, adipocytes, and myoblasts. Regulation of differentiation SRM University, Kattankulathur 603 203, Tamil Nadu, India of MSCs into osteogenic lineage is critical for maintaining bone mass and is necessary for prevention of bone related diseases. It is now evident that osteoblast differentiation is Abstract tightly controlled by several regulators including miRNAs The central dogma of transfer of genetic information from (Abdallah and Kassem, 2008; Guo et al., 2008; Lian DNA to protein via mRNA is now challenged by small et al., 2012), and miRNAs can regulate expression of fragment of non coding RNAs typically 19-25 nucleotides genes during differentiation of MSCs towards osteoblastic in length namely microRNAs (miRNAs). miRNAs regulate cells, resulting in bone formation (Taipaleenma¨ki et al., expression of the protein coding genes by interfering in their 2012). In the current review we discuss and summarize mRNAs and, thus, act as key regulators of diverge cellular miRNAs’ synthesis including their genomic position, target activities. Osteoblast differentiation, a key step in skeletal recognition, and gene regulation, and control of MSCs development involves activation of several signalling differentiation
    [Show full text]