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VOL. 73 (2), 537-566, 2007 ECTO-NUCLEOTIDASES, MOLECULAR PROPERTIES...

targeted deletion of the respective gene. The addition of the soluble
ATP- and ADP hydrolyzing enzyme apyrase can corroborate the
involvement of nucleotide signaling but does not provide immediate
evidence for a participation of endogenous ecto-nucleotidases.

TARGETED DELETION OF ECTO-NUCLEOTIDASES

The targeted deletion of NTPDase1 has yielded important insight
into the functional role of NTPDase1 in vascular control (88) and in
the immune system (89). Inactivation of mouse intestinal alkaline
phosphatase (IAP) revealed a functional involvement in fat
absorption (90). Knockout mice for NPP1 have been characterized in
addition to a natural mutant of NPP1 (tiptoe walking mouse).
Deficiency of NPP1 is associated with pathological calcification of
ligaments and joint capsules (42). Mutations in the TNAP gene in
humans cause hypophosphatasia involving defective mineralization
of hard tissue. Mice lacking TNAP can serve as a model for the
infantile form of hypophosphatasia and also reveal deficiencies in
nervous system development and a number of severe tissue
abnormalities (91, 92). Knockouts of the embryonic form of alkaline
phosphatase or double knockouts for TNAP and the embryonic form
do not reveal additional phenotypes (91). Double knockouts for TNAP
and NPP1 underline the opposing and reciprocal actions of NPP1
and TNAP in the production and hydrolysis of extracellular PPi and
thus in the control of bone mineralization, respectively. They suggest
that both TNAP and NPP1 are potential therapeutic targets for the
treatment of mineralization disorders (44, 93, 94). These effects on
mineralization appear to reflect the balance of extracellular PPi and
Pi levels controlled by the two enzymes rather than P2 or P1 receptor-
mediated mechanisms.

NPP2 (autotaxin) knockouts die at embryonic age and
investigations on heterozygous mice underline the notion that
phospholipase D activity and thus the production of lysophosphatidic
acid represents a major functional role of the enzyme (95). Mice in
which the ecto-5’-nucleotidase gene is disrupted do not reveal an
apparent phenotype when kept under normal conditions but detailed
studies corroborated the physiological importance of the enzyme in

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