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.

journal_name

Blood

journal_title

Blood

authors

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 A

doi

10.1182/blood-2009-03-209221

subject

Has Abstract

pub_date

2009-10-08 00:00:00

pages

3216-26

issue

15

eissn

0006-4971

issn

1528-0020

pii

blood-2009-03-209221

journal_volume

114

pub_type

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