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Am J Physiol Regul Integr Comp Physiol 279: R1365-R1377, 2000;
0363-6119/00 $5.00
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Vol. 279, Issue 4, R1365-R1377, October 2000

Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and regulates PC-1

K. A. Johnson1, L. Hessle2,3, S. Vaingankar1, C. Wennberg2,3, S. Mauro2, S. Narisawa2, J. W. Goding4, K. Sano5, J. L. Millan2,3, and R. Terkeltaub1

1 Veterans Affairs Medical Center/University of California San Diego, La Jolla 92161; 2 Burnham Institute, La Jolla, California 92037; 4 Monash Medical School, Prahran, Australia 3181; 3 Medical Biosciences, Medical Genetics, Umea University, Umea S-90185, Sweden; and 5 Kobe University, Kobe 650-0017, Japan

Tissue-nonspecific alkaline phosphatase (TNAP) is essential for bone matrix mineralization, but the central mechanism for TNAP action remains undefined. We observed that ATP-dependent 45Ca precipitation was decreased in calvarial osteoblast matrix vesicle (MV) fractions from TNAP-/- mice, a model of infantile hypophosphatasia. Because TNAP hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PPi), we assessed phosphodiesterase nucleotide pyrophosphatase (PDNP/NTPPPH) activity, which hydrolyzes ATP to generate PPi. Plasma cell membrane glycoprotein-1 (PC-1), but not the isozyme B10 (also called PDNP3) colocalized with TNAP in osteoblast MV fractions and pericellular matrix. PC-1 but not B10 increased MV fraction PPi and inhibited 45Ca precipitation by MVs. TNAP directly antagonized inhibition by PC-1 of MV-mediated 45Ca precipitation. Furthermore, the PPi content of MV fractions was greater in cultured TNAP-/- than TNAP+/+ calvarial osteoblasts. Paradoxically, transfection with wild-type TNAP significantly increased osteoblast MV fraction NTPPPH. Specific activity of NTPPPH also was twofold greater in MV fractions of osteoblasts from TNAP+/+ mice relative to TNAP-/- mice. Thus TNAP attenuates PC-1/NTPPPH-induced PPi generation that would otherwise inhibit MV-mediated mineralization. TNAP also paradoxically regulates PC-1 expression and NTPPPH activity in osteoblasts.

inorganic pyrophosphate; hypophosphatasia; PDNP3; B10; transglutaminase


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