1. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency
- Author
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Anna Villa, Maria Grazia Roncarolo, Emanuela Mrak, Filippo Carlucci, Maria Célia Cervi, Elena Zacchi, Alessandro Rubinacci, Eyal Grunebaum, Chaim M. Roifman, Aisha V. Sauer, Francesco Cavani, Alessandro Aiuti, Alessandro Ambrosi, Miriam Casiraghi, Raisa Jofra Hernandez, Sauer, Av, Mrak, E, Hernandez, Rj, Zacchi, E, Cavani, F, Casiraghi, M, Grunebaum, E, Roifman, Cm, Cervi, Mc, Ambrosi, Alessandro, Carlucci, F, Roncarolo, MARIA GRAZIA, Villa, A, Rubinacci, A, and Aiuti, Alessandro
- Subjects
Male ,Adenosine Deaminase ,Genetic enhancement ,Biochemistry ,SEVERE COMBINED IMMUNODEFICIENCY ,Osteogenesis ,Bone cell ,DYSPLASIA ,Mice, Knockout ,PRECURSORS ,Mice, Inbred BALB C ,biology ,Hematopoietic Stem Cell Transplantation ,Osteoblast ,Hematology ,medicine.anatomical_structure ,RANKL ,Female ,medicine.medical_specialty ,Immunology ,ADA SCID RANKL OPG immunodeficiency bone mice ,Bone and Bones ,ENZYME-REPLACEMENT ,Osteoprotegerin ,Internal medicine ,medicine ,Animals ,Humans ,Transplantation, Homologous ,HEMATOPOIETIC STEM-CELLS ,MARROW-TRANSPLANTATION ,ADENOSINE-DEAMINASE DEFICIENCY ,GENE-THERAPY ,IMMUNE-SYSTEM ,MICE ,Settore MED/38 - Pediatria Generale e Specialistica ,Severe combined immunodeficiency ,Osteoblasts ,RANK Ligand ,Cell Biology ,Genetic Therapy ,medicine.disease ,Hematopoietic Stem Cells ,Adenosine deaminase deficiency ,Hematopoiesis ,Endocrinology ,biology.protein ,Bone marrow - 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-κB 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 and #NCT00599781.
- Published
- 2009