1. Skeletal Mineralization Deficits and Impaired Biogenesis and Function of Chondrocyte-Derived Matrix Vesicles in Phospho1(-/-) and Phospho1/Pi t1 Double-Knockout Mice.

    Journal of Bone and Mineral Research 31(6):1275 (2016) PMID 26773408 PMCID PMC4891278

    We have previously shown that ablation of either the Phospho1 or Alpl gene, encoding PHOSPHO1 and tissue-nonspecific alkaline phosphatase (TNAP) respectively, lead to hyperosteoidosis, but that their chondrocyte-derived and osteoblast-derived matrix vesicles (MVs) are able to initiate mineraliza...
  2. Alkaline Phosphatase and Hypophosphatasia.

    Calcified Tissue International 98(4):398 (2016) PMID 26590809 PMCID PMC4824800

    Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PPi), a natural substrate of TNAP and potent inhibitor of mineralization. Thus, HPP f...
  3. Phosphate induces formation of matrix vesicles during odontoblast-initiated mineralization in vitro.

    Matrix Biology 52-54:284 (2016) PMID 26883946 PMCID PMC4875887

    Mineralization is a process of deposition of calcium phosphate crystals within a fibrous extracellular matrix (ECM). In mineralizing tissues, such as dentin, bone and hypertrophic cartilage, this process is initiated by a specific population of extracellular vesicles (EV), called matrix vesicles...
  4. Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector.

    Molecular therapy. Methods & clinical development 3:15059 (2016) PMID 26904710 PMCID PMC4739158

    Hypophosphatasia (HPP) is an inherited disease caused by genetic mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). This results in defects in bone and tooth mineralization. We recently demonstrated that TNALP-deficient (Akp2 (-/-) ) mice, which mimic the phenotype o...
  5. The functional co-operativity of tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 during initiation of skeletal mineralization.

    Biochemistry and Biophysics Reports 4:196 (2015)

    Phosphatases are recognized to have important functions in the initiation of skeletal mineralization. Tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 are indispensable for bone and cartilage mineralization but their functional relationship in the mineralization process rema...
  6. Prevention of Lethal Murine Hypophosphatasia by Neonatal Ex Vivo Gene Therapy Using Lentivirally Transduced Bone Marrow Cells.

    Human Gene Therapy 26(12):801 (2015) PMID 26467745

    Hypophosphatasia (HPP) is an inherited skeletal and dental disease caused by loss-of-function mutations in the gene that encodes tissue-nonspecific alkaline phosphatase (TNALP). The major symptoms of severe forms of the disease are bone defects, respiratory insufficiency, and epileptic seizures....
  7. Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing.

    Molecular Genetics and Metabolism 116(3):215 (2015) PMID 26432670

    Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of...
  8. Proteoliposomes with the ability to transport Ca(2+) into the vesicles and hydrolyze phosphosubstrates on their surface.

    Archives of Biochemistry and Biophysics 584:79 (2015) PMID 26325078

    We describe the production of stable DPPC and DPPC:DPPS-proteoliposomes harboring annexin V (AnxA5) and tissue-nonspecific alkaline phosphatase (TNAP) and their use to investigate whether the presence of AnxA5 impacts the kinetic parameters for hydrolysis of TNAP substrates at physiological pH. ...
  9. Enzyme replacement for craniofacial skeletal defects and craniosynostosis in murine hypophosphatasia.

    Bone 78:203 (2015) PMID 25959417 PMCID PMC4466206

    Hypophosphatasia (HPP) is an inborn-error-of-metabolism disorder characterized by deficient bone and tooth mineralization due to loss-of function mutations in the gene (Alpl) encoding tissue-nonspecific alkaline phosphatase (TNAP). Alpl(-/-) mice exhibit many characteristics seen in infantile HP...
  10. Effects of etidronate on the Enpp1⁻/⁻ mouse model of generalized arterial calcification of infancy.

    International Journal of Molecular Medicine 36(1):159 (2015) PMID 25975272 PMCID PMC4494596

    Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder of spontaneous infantile arterial and periarticular calcification which is attributed to mutations in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) gene. Whilst the bisphosphonate, etidronate...
  11. An investigation of the mineral in ductile and brittle cortical mouse bone.

    Journal of Bone and Mineral Research 30(5):786 (2015) PMID 25418329 PMCID PMC4507744

    Bone is a strong and tough material composed of apatite mineral, organic matter, and water. Changes in composition and organization of these building blocks affect bone's mechanical integrity. Skeletal disorders often affect bone's mineral phase, either by variations in the collagen or directly ...
  12. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification.

    Journal of Bone and Mineral Research 30(5):824 (2015) PMID 25428889 PMCID PMC4406354

    Medial vascular calcification (MVC) is a pathological phenomenon that causes vascular stiffening and can lead to heart failure; it is common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases. These conditions share the ...
  13. Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl-/- mice by administration of soluble (non-targeted) chimeric alkaline phosphatase.

    Bone 72:137 (2015) PMID 25433339 PMCID PMC4283789

    Hypophosphatasia (HPP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization that is also a natural substrate of TNAP, in the extracellular space. HPP cause...
  14. A robust transcriptional program in newts undergoing multiple events of lens regeneration throughout their lifespan.

    eLife 4 (2015) PMID 26523389 PMCID PMC4739772

    Newts have the ability to repeatedly regenerate their lens even during ageing. However, it is unclear whether this regeneration reflects an undisturbed genetic activity. To answer this question, we compared the transcriptomes of lenses, irises and tails from aged newts that had undergone lens re...
  15. What Can We Learn About the Neural Functions of TNAP from Studies on Other Organs and Tissues?

    Sub-Cellular Biochemistry 76:155 (2015) PMID 26219711

    To-date, the function of tissue-nonspecific alkaline phosphatase (TNAP) has largely been defined through studies in patients and mice affected by hypophosphatasia (HPP), a rare inborn-error-of-metabolism caused by mutation(s) in the TNAP gene (ALPL). The skeletal disease in HPP can be explained ...
  16. Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase.

    PLoS ONE 10(3):e0119874 (2015) PMID 25775211 PMCID PMC4361680

    The conserved active site of alkaline phosphatases (AP) contains catalytically important Zn2+ (M1 and M2) and Mg2+-sites (M3) and a fourth peripheral Ca2+ site (M4) of unknown significance. We have studied Ca2+ binding to M1-4 of tissue-nonspecific AP (TNAP), an enzyme crucial for skeletal miner...
  17. Intestinal alkaline phosphatase deficiency leads to lipopolysaccharide desensitization and faster weight gain.

    Infection and Immunity 83(1):247 (2015) PMID 25348635 PMCID PMC4288875

    Animals develop in the presence of complex microbial communities, and early host responses to these microbes can influence key aspects of development, such as maturation of the immune system, in ways that impact adult physiology. We previously showed that the zebrafish intestinal alkaline phosph...
  18. Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease.

    Computational and Structural Biotechnology Journal 13:95 (2015) PMID 25709758 PMCID PMC4334957

    Tissue-nonspecific alkaline phosphatase (TNAP) is one of the four isozymes in humans and mice that have the capacity to hydrolyze phosphate groups from a wide spectrum of physiological substrates. Among these, TNAP degrades substrates implicated in neurotransmission. Transgenic mice lacking TNAP...
  19. The critical role of membralin in postnatal motor neuron survival and disease.

    eLife 4 (2015) PMID 25977983 PMCID PMC4460860

    Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5-6. Selective death of lower motor neurons, including those innervating the limbs,...
  20. Reference point indentation is not indicative of whole mouse bone measures of stress intensity fracture toughness.

    Bone 69:174 (2014) PMID 25280470 PMCID PMC4228060

    Bone fragility is a concern for aged and diseased bone. Measuring bone toughness and understanding fracture properties of the bone are critical for predicting fracture risk associated with age and disease and for preclinical testing of therapies. A reference point indentation technique (BioDent)...