Differential deoxyadenosine toxicity to immature rabbit cartilage in vitro. a model for the chondro‐osseous dysplasia of adenosine deaminase deficiency

Abstract

Deoxyadenosine metabolism was investigated in rabbit growth plate and articular cartilage to elucidate the biochemical basis for the chondro-osseous dysplasia observed in adenosine deaminase (ADA) deficiency. Models of ADA deficiency, the combination of deoxyadenosine and either of 2 ADA inhibitors, were selectively toxic to immature cartilage, supporting the hypothesis that the chondro-osseous dysplasia of ADA deficiency is the consequence of the enzyme deficiency. Depletion of ATP may play a role in the altered chondrocyte viability and function observed in this model.Adenosine deaminase (ADA) (EC 3.5.4.4) catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. An inherited deficiency of ADA causes an autosomal recessive form of severe combined immunodeficiency disease (1-3). Clinically, ADA-deficient individuals suffer from overwhelming infection and malabsorption. In addition to immune dysfunction, ADA-deficient individuals develop abnormalities in bone and cartilage, termed chondro-osseous dysplasia ( 4 6 ) , which is recognized by characteristic radiographic changes and is associated with a distinctive histopathologic pattern. Although the radiographic changes are not entirely specific, they are quite prevalent in chondro-osseous dysplasia and improve with successful enzyme replacement therapy (7,s).The absence of ADA activity results in the predictable increased concentrations of deoxyadenosine and adenosine in deficient individuals (9,lO). In vivo, the accumulation of deoxyadenosine leads to increased concentrations of deoxyATP in erythrocytes, peripheral blood lymphocytes, and bone marrow cells (10,ll). Precisely how the accumulation of these metabolites causes immune dysfunction is uncertain. Possibilities include inhibition of ribonucleotide reductase (EC 1.17.4.1) by deoxyATP (10,l I), inhibition and inactivation of S-adenosyl-L-homocysteine (SAH) hydrolase (EC 3.3.1.1) by adenosine and deoxyadenosine (12,131, and ATP depletion (1416). Also, deoxyadenosine and its metabolites have been observed to cause accumulation of DNA strand breaks (17,18), inhibit RNA synthesis (18,19), lower NAD pools (lS), and inhibit methionine synthesis (20).The metabolic abnormalities that cause the chondro-osseous dysplasia are also not understood. We have investigated the effects of ADA inhibition in vitro on chondrocyte viability and function. Our results support the hypothesis that the chondro-osseous dysplasia observed in ADA deficiency is the consequence of the disordered purine metabolism that results when ADA activity is absent, and suggest that ATP depletion may play a significant role in the pathogenesis of the cartilage and bone pathology observed.

Case 18-1998

“…My colleagues and I initially thought that the cartilaginous abnormalities associated with adenosine deaminase deficiency were due to inanition, 11 but studies in rabbits have shown that adenosine deaminase inhibitors cause the same cartilaginous abnormalities that are typically seen in human infants with adenosine deaminase deficiency. 12 Microscopical examination reveals that the chondrocytes swell, become necrotic, and are in disarray.…”