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Blood, 8 October 2009, Vol. 114, No. 15, pp. 3216-3226. Prepublished online as a Blood First Edition Paper on July 24, 2009; DOI 10.1182/blood-2009-03-209221. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-03-209221v1 114/15/3216    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Sauer, A. V. Articles by Aiuti, A. PubMed PubMed Citation Articles by Sauer, A. V. Articles by Aiuti, A. Related Collections Hematopoiesis and Stem Cells Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency Aisha V. Sauer1,2, Emanuela Mrak3, Raisa Jofra Hernandez1, Elena Zacchi3, Francesco Cavani4, Miriam Casiraghi5, Eyal Grunebaum6, Chaim M. Roifman6, Maria C. Cervi7, Alessandro Ambrosi8, Filippo Carlucci9, Maria Grazia Roncarolo1,2, Anna Villa1,10, Alessandro Rubinacci3, and Alessandro Aiuti1,11 1 San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; 2 Università Vita-Salute San Raffaele, Milan, Italy; 3 Bone Metabolic Unit, Scientific Institute San Raffaele, Milan, Italy; 4 Department for Anatomy and Histology, University of Modena, Modena, Italy; 5 Pediatric Clinical Research Unit, HSR-TIGET, Milan, Italy; 6 Division of Allergy and Clinical Immunology, Hospital for Sick Children, Toronto, ON; 7 Department of Puericultura and Pediatria, University of São Paulo, Ribeirão Preto, Brasil; 8 University Statistics Centre for Biomedical Sciences (CUSSB), San Raffaele University, Milan, Italy; 9 Institute for Biochemistry and Enzymology, University of Siena, Siena, Italy; 10 Consiglio Nazionale delle Ricerche Istituto Tecnologie Biomediche (ITB-CNR), Segrate, Milan, Italy; and 11 Department of Public Health and Cell Biology, Tor Vergata University, Rome, Italy Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-B ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA–severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children's growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 [ClinicalTrials.gov] and #NCT00599781 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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