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)
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...
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)
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...
Prevention of Lethal Murine Hypophosphatasia by Neonatal Ex Vivo Gene Therapy Using Lentivirally Transduced Bone Marrow Cells.
Human Gene Therapy 26(12):801 (2015)
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....
Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification.
Journal of Bone and Mineral Research 30(5):824 (2015)
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 ...
Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase.
PLoS ONE 10(3):e0119874 (2015)
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...
Genetically Modified Mice for Studying TNAP Function.
Sub-Cellular Biochemistry 76:45 (2015)
Genetically modified mice are powerful tools for understanding the functions of genes and proteins and often serve as models of human disease. Here, several knockout and transgenic mouse lines related to tissue-nonspecific alkaline phosphatase (TNAP) are described. Conventional TNAP knockout mic...
The critical role of membralin in postnatal motor neuron survival and disease.
eLife 4 (2015)
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,...
Ablation of osteopontin improves the skeletal phenotype of phospho1(-/-) mice.
Journal of Bone and Mineral Research 29(11):2369 (2014)
PHOSPHO1 and tissue-nonspecific alkaline phosphatase (TNAP) have nonredundant functions during skeletal mineralization. Although TNAP deficiency (Alpl(-/-) mice) leads to hypophosphatasia, caused by accumulation of the mineralization inhibitor inorganic pyrophosphate (PPi ), comparably elevated ...
A novel approach to maintain gut mucosal integrity using an oral enzyme supplement.
Annals of Surgery 260(4):706 (2014)
To determine the role of intestinal alkaline phosphatase (IAP) in enteral starvation-induced gut barrier dysfunction and to study its therapeutic effect as a supplement to prevent gut-derived sepsis.
Critically ill patients are at increased risk for systemic sepsis and, in some cases, multiorgan...
Sex-dependent, zinc-induced dephosphorylation of phospholamban by tissue-nonspecific alkaline phosphatase in the cardiac sarcomere.
American Journal of Physiology - Heart and Circ... 307(6):H933 (2014)
We have previously reported that Zn(2+) infused into the coronary arteries of isolated rat hearts leads to the potent dephosphorylation of phospholamban (PLB) as well as a noticeable but less potent dephosphorylation of the ryanodine receptor 2. We hypothesized in the present study that a Zn(2+)...
Vascular calcification is dependent on plasma levels of pyrophosphate.
Kidney International 85(6):1351 (2014)
Plasma levels of pyrophosphate, an endogenous inhibitor of vascular calcification, are reduced in end-stage renal disease and correlate inversely with arterial calcification. However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue l...
Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates.
American Journal of Physiology - Gastrointestin... 306(10):G826 (2014)
The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aime...
Identification of a selective inhibitor of murine intestinal alkaline phosphatase (ML260) by concurrent ultra-high throughput screening against human and mouse isozymes.
Bioorganic & Medicinal Chemistry Letters 24(3):1000 (2014)
Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to man and are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. In humans, four AP isozymes have been identified-one tissue-nonspecific (TNAP) and three tissue-...
In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin.
Journal of Bone and Mineral Research 28(7):1587 (2013)
Functional ablation of tissue-nonspecific alkaline phosphatase (TNAP) (Alpl⁻/⁻ mice) leads to hypophosphatasia, characterized by rickets/osteomalacia attributable to elevated levels of extracellular inorganic pyrophosphate, a potent mineralization inhibitor. Osteopontin (OPN) is also elevated in...
Intestinal alkaline phosphatase prevents metabolic syndrome in mice.
PNAS 110(17):7003 (2013)
Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for...
Isozyme profile and tissue-origin of alkaline phosphatases in mouse serum.
Bone 53(2):399 (2013)
Mouse serum alkaline phosphatase (ALP) is frequently measured and interpreted in mammalian bone research. However, little is known about the circulating ALPs in mice and their relation to human ALP isozymes and isoforms. Mouse ALP was extracted from liver, kidney, intestine, and bone from verteb...
Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate.
American Journal of Physiology - Gastrointestin... 304(6):G597 (2013)
Uridine diphosphate (UDP) is a proinflammatory nucleotide implicated in inflammatory bowel disease. Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor capable of inhibiting intestinal inflammation. We used the malachite green assay to show that IAP dephosphorylates UDP. To stu...
Osteoconductivity and osteoinductivity of NanoFUSE(®) DBM.
Cell and Tissue Banking 14(1):33 (2013)
Bone graft substitutes have become an essential component in a number of orthopedic applications. Autologous bone has long been the gold standard for bone void fillers. However, the limited supply and morbidity associated with using autologous graft material has led to the development of many di...
The use of tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 inhibitors to affect mineralization by cultured cells.
Methods in Molecular Biology 1053:125 (2013)
Here, we describe methods to evaluate the ability of small molecules inhibitors of TNAP and PHOSPHO1 in preventing mineralization of primary cultures of murine vascular smooth muscle cells. The procedures are also applicable to primary cultures of calvarial osteoblasts. These cell-based assays a...
Mechanical and biocompatible characterization of a cross-linked collagen-hyaluronic acid wound dressing.
Biomatter 3(4) (2013)
Collagen scaffolds have been widely employed as a dermal equivalent to induce fibroblast infiltrations and dermal regeneration in the treatment of chronic wounds and diabetic foot ulcers. Cross-linking methods have been developed to address the disadvantages of the rapid degradation associated w...