ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency

Blood. 2009 Oct 8;114(15):3216-26. doi: 10.1182/blood-2009-03-209221. Epub 2009 Jul 24.

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.

Trial registration: ClinicalTrials.gov NCT00598481 NCT00599781.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase*
  • Animals
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Female
  • Genetic Therapy
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / enzymology
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Osteoblasts / metabolism*
  • Osteogenesis*
  • Osteoprotegerin / blood*
  • Osteoprotegerin / genetics
  • RANK Ligand / blood*
  • RANK Ligand / genetics
  • Severe Combined Immunodeficiency / blood*
  • Severe Combined Immunodeficiency / pathology
  • Severe Combined Immunodeficiency / therapy*
  • Transplantation, Homologous

Substances

  • Osteoprotegerin
  • RANK Ligand
  • TNFRSF11B protein, human
  • TNFSF11 protein, human
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • Adenosine Deaminase

Associated data

  • ClinicalTrials.gov/NCT00598481
  • ClinicalTrials.gov/NCT00599781