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.
journal_name
Bloodjournal_title
Bloodauthors
Sauer AV,Mrak E,Hernandez RJ,Zacchi E,Cavani F,Casiraghi M,Grunebaum E,Roifman CM,Cervi MC,Ambrosi A,Carlucci F,Roncarolo MG,Villa A,Rubinacci A,Aiuti Adoi
10.1182/blood-2009-03-209221subject
Has Abstractpub_date
2009-10-08 00:00:00pages
3216-26issue
15eissn
0006-4971issn
1528-0020pii
blood-2009-03-209221journal_volume
114pub_type
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