title: ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency.
abstract: 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-kappaB 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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
authors.forename: Aisha V
authors.initials: AV
authors.lastname: Sauer
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mrak
authors.forename: Raisa Jofra
authors.initials: RJ
authors.lastname: Hernandez
authors.forename: Elena
authors.initials: E
authors.lastname: Zacchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavani
authors.forename: Miriam
authors.initials: M
authors.lastname: Casiraghi
authors.forename: Eyal
authors.initials: E
authors.lastname: Grunebaum
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cervi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ambrosi
authors.forename: Filippo
authors.initials: F
authors.lastname: Carlucci
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rubinacci
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
mesh_terms: D000243:Adenosine Deaminase; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D053244:Osteoprotegerin / Q000097:blood* / Q000235:genetics; D053245:RANK Ligand / Q000097:blood* / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000097:blood* / Q000473:pathology / Q000628:therapy*; D014184:Transplantation, Homologous
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D000243:Adenosine Deaminase