Hypophosphatasia is a heritable, untreatable, bone mineralization disease of variable clinical severity and pattern of inheritance caused by mutations that affect the tissue-nonspecific alkaline phosphatase (TNAP) gene. TNAP's primary function in bone is to hydrolyze inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. The elevated levels of PPi that accumulate in hypophosphatasia cause a secondary increase in the levels of osteopontin (OPN), another mineralization inhibitor, which likely contributes to the resulting rickets/osteomalacia characteristic of this disease. The genetic ablation of the molecules that produce and transport PPi to the extracellular space, i.e., NPP1 and ANK, lead to normalization of the extracellular PPi and OPN levels, resulting in the reversal of rickets/osteomalacia in the Akp2 (TNAP) knockout mice.
In Aim 1 we will test the hypothesis that we can use chemical inhibitors to therapeutically target the function of NPP1 and ANK to cause normalization of both PPi and OPN levels and thus, achieve correction of the bone abnormalities of hypophosphatasia. We will also ascertain to what extent increased OPN levels contribute to the rickets/osteomalacia by examining the degree of correction that might be achieved in Akp2/OPN double deficient mice. We will also continue with our ongoing efforts to treat hypophosphatasia by cell/gene therapy. Elucidating the molecular basis of monomer-monomer crosstalk in TNAP heterodimers is crucial to our ability to understand and predict the severity of TNAP-mutant combinations and the mechanism(s) of pathogenesis, penetrance, expressivity and mode of inheritance for each mutation.
In Specific Aim 2, we will clarify how each structural domain in the TNAP subunit contributes to the allosteric behavior of TNAP dimers and how they affect the kinetic properties of TNAP heterodimers towards the physiological substrates PLP, PPi and AMP. Also, since TNAP itself may be a useful therapeutic target to treat hvpermineralization disorders, we will elucidate the precise mechanism of TNAP inhibition to help us design more specific enzyme inhibitors for the clinical management of diseases such as ankylosis and osteoarthritis. Our work will provide fundamental information about the molecular mechanism(s) of pathogenesis of hypophosphatasia and the molecular basis for the different genetic modes of transmission. We also have a unique opportunity to develop successful treatments for hypophosphatasia and other bone diseases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012889-08
Application #
6998924
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Shum, Lillian
Project Start
1999-03-01
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
8
Fiscal Year
2006
Total Cost
$419,652
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Pettengill, Matthew; Matute, Juan D; Tresenriter, Megan et al. (2018) Correction: Human alkaline phosphatase dephosphorylates microbial products and is elevated in preterm neonates with a history of late-onset sepsis. PLoS One 13:e0197532
Li, Qiaoli; Huang, Jianhe; Pinkerton, Anthony B et al. (2018) Inhibition of Tissue-Nonspecific Alkaline Phosphatase Attenuates Ectopic Mineralization in the Abcc6-/- Mouse Model of PXE but Not in the Enpp1 Mutant Mouse Models of GACI. J Invest Dermatol :
Yang, Won Ho; Heithoff, Douglas M; Aziz, Peter V et al. (2018) Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis. Cell Host Microbe 24:500-513.e5
Patel, Jessal J; Zhu, Dongxing; Opdebeeck, Britt et al. (2018) Inhibition of arterial medial calcification and bone mineralization by extracellular nucleotides: The same functional effect mediated by different cellular mechanisms. J Cell Physiol 233:3230-3243
Simão, Ana Maria Sper; Bolean, Maytê; Favarin, Bruno Zoccaratto et al. (2018) Lipid microenvironment affects the ability of proteoliposomes harboring TNAP to induce mineralization without nucleators. J Bone Miner Metab :
Foster, B L; Ao, M; Salmon, C R et al. (2018) Osteopontin regulates dentin and alveolar bone development and mineralization. Bone 107:196-207
Brun, Lucas R; Lombarte, M; Roma, S et al. (2018) Increased calcium uptake and improved trabecular bone properties in intestinal alkaline phosphatase knockout mice. J Bone Miner Metab 36:661-667
Bottini, Massimo; Mebarek, Saida; Anderson, Karen L et al. (2018) Matrix vesicles from chondrocytes and osteoblasts: Their biogenesis, properties, functions and biomimetic models. Biochim Biophys Acta Gen Subj 1862:532-546
Morcos, M W; Al-Jallad, H; Li, J et al. (2018) PHOSPHO1 is essential for normal bone fracture healing: An Animal Study. Bone Joint Res 7:397-405
Huang, Nai-Jia; Lin, Ying-Cing; Lin, Chung-Yueh et al. (2018) Enhanced phosphocholine metabolism is essential for terminal erythropoiesis. Blood 131:2955-2966

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