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rdf:type |
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lifeskim:mentions |
umls-concept:C0029418,
umls-concept:C0031437,
umls-concept:C0085110,
umls-concept:C0205369,
umls-concept:C0262950,
umls-concept:C0332281,
umls-concept:C1336645,
umls-concept:C1367028,
umls-concept:C1412836,
umls-concept:C1710303,
umls-concept:C1880022
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pubmed:issue |
15
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pubmed:dateCreated |
2009-10-9
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pubmed:databankReference |
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Deaminase,
http://linkedlifedata.com/resource/pubmed/chemical/Osteoprotegerin,
http://linkedlifedata.com/resource/pubmed/chemical/RANK Ligand,
http://linkedlifedata.com/resource/pubmed/chemical/TNFRSF11B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/TNFSF11 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Tnfrsf11b protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Tnfsf11 protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1528-0020
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pubmed:author |
pubmed-author:AiutiAlessandroA,
pubmed-author:AmbrosiAlessandroA,
pubmed-author:CarlucciFilippoF,
pubmed-author:CasiraghiMiriamM,
pubmed-author:CavaniFrancescoF,
pubmed-author:CerviMaria CMC,
pubmed-author:GrunebaumEyalE,
pubmed-author:HernandezRaisa JofraRJ,
pubmed-author:MrakEmanuelaE,
pubmed-author:RoifmanChaim MCM,
pubmed-author:RoncaroloMaria GraziaMG,
pubmed-author:RubinacciAlessandroA,
pubmed-author:SauerAisha VAV,
pubmed-author:VillaAnnaA,
pubmed-author:ZacchiElenaE
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pubmed:issnType |
Electronic
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pubmed:day |
8
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pubmed:volume |
114
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3216-26
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pubmed:meshHeading |
pubmed-meshheading:19633200-Adenosine Deaminase,
pubmed-meshheading:19633200-Animals,
pubmed-meshheading:19633200-Bone and Bones,
pubmed-meshheading:19633200-Female,
pubmed-meshheading:19633200-Gene Therapy,
pubmed-meshheading:19633200-Hematopoiesis,
pubmed-meshheading:19633200-Hematopoietic Stem Cell Transplantation,
pubmed-meshheading:19633200-Hematopoietic Stem Cells,
pubmed-meshheading:19633200-Humans,
pubmed-meshheading:19633200-Male,
pubmed-meshheading:19633200-Mice,
pubmed-meshheading:19633200-Mice, Inbred BALB C,
pubmed-meshheading:19633200-Mice, Knockout,
pubmed-meshheading:19633200-Osteoblasts,
pubmed-meshheading:19633200-Osteogenesis,
pubmed-meshheading:19633200-Osteoprotegerin,
pubmed-meshheading:19633200-RANK Ligand,
pubmed-meshheading:19633200-Severe Combined Immunodeficiency,
pubmed-meshheading:19633200-Transplantation, Homologous
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pubmed:year |
2009
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pubmed:articleTitle |
ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency.
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pubmed:affiliation |
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Multicenter Study,
Clinical Trial, Phase II,
Clinical Trial, Phase I
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