title: Abnormal vitamin B6 metabolism in alkaline phosphatase knock-out mice causes multiple abnormalities, but not the impaired bone mineralization.
abstract: The tissue non-specific alkaline phosphatase (TNAP) knock-out mouse is a model of infantile hypophosphatasia displaying impaired bone mineralization, epileptic seizures, apnoea, abnormal apoptosis in the thymus, abnormal lumbar nerve roots, and postnatal death. Administration of vitamin B6 suppresses the epileptic seizures in TNAP-/- mice. This paper examines to what extent the diverse abnormalities seen in these mice are due to impaired utilization of vitamin B6, using two complementary approaches: administration of vitamin B6 to TNAP null mice and deprivation of vitamin B6 in wild-type and TNAP heterozygous mice. Administration of exogenous pyridoxal HCl delayed the onset of epileptic attacks and increased the life span of TNAP-/- mice. The episodes of apnoea ceased and the appearance of lumbar nerve roots improved, but hypomineralization and accumulation of osteoid continued to worsen with age. Control mice fed a vitamin B6-depleted diet developed epileptic seizures indistinguishable from those observed in TNAP-/- mice, abnormal apoptosis in the thymus, and thinning of the nerve roots, but showed no evidence of bone mineralization abnormalities. Depletion of vitamin B6 did not affect the ability of primary cultures of osteoblasts to deposit bone mineral in vitro. While abnormal metabolism of vitamin B6 explains many of the abnormalities in this mouse model of infantile hypophosphatasia, it is not the basis of the abnormal mineralization that characterizes this disease.
authors.affiliation: The Burnham Institute, La Jolla Cancer Research Center, La Jolla, CA 92037, USA.
authors.forename: S
authors.initials: S
authors.lastname: Narisawa
authors.forename: C
authors.initials: C
authors.lastname: Wennberg
authors.forename: J L
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000015:Abnormalities, Multiple / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000235:genetics / Q000502:physiology; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology*; D018929:Cell Culture Techniques; D004827:Epilepsy / Q000209:etiology / Q000517:prevention & control; D006128:Growth / Q000187:drug effects; D007014:Hypophosphatasia / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology; D011730:Pyridoxal / Q000494:pharmacology; D011736:Pyridoxine / Q000378:metabolism*; D026681:Vitamin B 6 Deficiency / Q000150:complications
chemical_list: D011730:Pyridoxal; D000469:Alkaline Phosphatase; D011736:Pyridoxine