Affinage

Showing ALPL — TNAP is a alias.

ALPL

Alkaline phosphatase, tissue-nonspecific isozyme · UniProt P05186

Length
524 aa
Mass
57.3 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALPL (TNAP/TNSALP) encodes a broad-specificity ectoenzyme whose principal physiological role is to hydrolyze extracellular phosphate-bearing substrates—most prominently inorganic pyrophosphate (PPi) and ATP/ADP—thereby controlling the local mineralization milieu and extracellular nucleotide tone across skeletal, vascular, and neural tissues (PMID:19874193, PMID:27932058). In matrix vesicles it is the dominant hydrolase of ATP, ADP, and PPi, and by depleting the mineralization inhibitor PPi it drives hydroxyapatite formation, acting non-redundantly with PHOSPHO1 such that simultaneous loss of both essentially abolishes matrix mineralization (PMID:19874193, PMID:26457330, PMID:25504209). This PPi-clearing activity underlies its role in skeletal and craniofacial development—Alpl-deficient mice show craniosynostosis, impaired cranial base growth with diminished MAPK signaling and altered chondrocyte maturation, and disrupted MSC fate via elevated extracellular ATP and AMPKα inactivation (PMID:25014884, PMID:28377728, PMID:30210899); conversely, ectopic or excess TNAP activity is sufficient to drive vascular and ectopic calcification, including endothelial-driven arterial calcification, VSMC trans-differentiation via PPi hydrolysis and BMP-2 induction, and pathologic mineralization in CD73-deficient and ankylosing-spondylitis settings (PMID:26675253, PMID:27932058, PMID:27965423, PMID:31682238). Full catalytic activation requires zinc metalation in the early secretory pathway, supplied cooperatively by ZnT5–ZnT6/ZnT7 complexes through a di-proline motif in luminal loop 2 and by cytoplasmic zinc handling via ZnT1, metallothionein, and ZnT4 (PMID:24204829, PMID:27303047). Beyond mineralization, TNAP regulates extracellular nucleotide and neurotransmitter levels at synaptic clefts and nodes of Ranvier and is required for normal myelination and synaptogenesis (PMID:26219708, PMID:22696173, PMID:29551976); it dephosphorylates extracellular hyperphosphorylated tau to generate an M1/M3 muscarinic agonist that drives neuronal death in tauopathy (PMID:35065251). In adipocytes a mitochondrial pool of TNAP acts as a phosphocreatine phosphatase initiating a thermogenic futile creatine cycle downstream of adrenergic/Gαq signaling, with adipocyte-specific ablation causing reduced energy expenditure and obesity (PMID:33981039, PMID:36344764). TNAP also modulates TGF-β/SMAD2/3 fibrotic signaling by interacting with and dephosphorylating SMAD2/3 (PMID:31289197). Its expression is controlled by a Dhx36–HDAC1/4 transcriptional axis and by androgen receptor signaling (PMID:21590736, PMID:18838539), and on brain vascular endothelium ALPL serves as a receptor mediating transcytosis of an engineered AAV vector across the blood-brain barrier (PMID:40340250).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2010 High

    Established which enzyme dominates substrate turnover in the mineralizing matrix vesicle, answering whether TNAP or NPP1/PHOSPHO1 is the principal hydrolase of ATP, ADP, and PPi.

    Evidence Kinetic substrate-hydrolysis assays on matrix vesicles from TNAP-, NPP1-, and PHOSPHO1-deficient osteoblasts

    PMID:19874193

    Open questions at the time
    • Does not define the relative tissue-specific contribution outside matrix vesicles
    • Does not address how product (Pi/PPi) ratios are spatially controlled
  2. 2011 Medium

    Defined a transcriptional control circuit for ALPL, showing Dhx36 activates the promoter while HDAC1/4 repress it through a deacetylase-independent mechanism.

    Evidence Promoter luciferase deletion constructs, DNA affinity precipitation, Co-IP, and forced HDAC expression

    PMID:21590736

    Open questions at the time
    • The deacetylase-independent repression mechanism is not molecularly resolved
    • Tissue contexts where this axis operates are not defined
  3. 2013 High

    Resolved how TNAP catalytic competence is acquired, showing zinc supply for activation comes from a cytoplasmic ZnT1/metallothionein/ZnT4 pathway distinct from direct luminal zinc loading.

    Evidence Triple-knockout cells with mutant reconstitution and TNAP activity assays

    PMID:24204829

    Open questions at the time
    • Stoichiometry and order of zinc loading onto TNAP not defined
    • Does not establish the structural metalation intermediate
  4. 2016 High

    Identified the molecular feature on zinc transporters required for TNAP maturation, showing a di-proline motif in ZnT5/ZnT7 luminal loop 2 mediates activation independently of zinc transport.

    Evidence PP-to-AA point mutants reconstituted in ZnT5-ZnT6/ZnT7 triple-knockout cells with activity and zinc-rescue assays

    PMID:27303047

    Open questions at the time
    • Direct physical contact between the PP-motif and TNAP not shown
    • Structural basis of metalation chaperoning unresolved
  5. 2015 Medium

    Demonstrated non-redundant cooperation between TNAP and PHOSPHO1 in initiating mineralization, clarifying why single-enzyme loss is insufficient to block matrix mineralization.

    Evidence Combined and individual pharmacological inhibition with PHOSPHO1 overexpression in osteoblasts and metatarsal cultures

    PMID:26457330

    Open questions at the time
    • The spatial/temporal hand-off between the two enzymes is not mapped
    • Relies partly on pharmacological inhibitors rather than genetic ablation
  6. 2014 Medium

    Showed a cell-autonomous role for TNAP in craniofacial bone, linking its loss to aberrant osteoblast behavior and craniosynostosis.

    Evidence Alpl-/- mouse micro-CT/histology plus TNAP shRNA knockdown in calvarial cells with proliferation/apoptosis/adhesion readouts

    PMID:25014884

    Open questions at the time
    • Whether enzymatic activity alone accounts for cell-adhesion and proliferation changes is unclear
    • Downstream effectors of the gene-expression changes are not identified
  7. 2017 Medium

    Placed TNAP upstream of MAPK in chondrocyte maturation, explaining the cranial base growth defect and confirming it is rescuable by enzyme replacement.

    Evidence Alpl-/- chondrocyte signaling analysis with mineral-targeted recombinant TNAP rescue in vivo

    PMID:28377728

    Open questions at the time
    • Mechanistic link between extracellular substrate hydrolysis and intracellular MAPK is undefined
    • Single lab
  8. 2018 Medium

    Connected TNAP to MSC cell fate, showing its loss elevates extracellular and intracellular ATP and inactivates AMPKα, biasing differentiation toward senescence/adipogenesis.

    Evidence Alpl knockout/knockdown MSCs with ATP measurements, AMPKα analysis, and metformin rescue in Alpl+/- mice

    PMID:30210899

    Open questions at the time
    • The route by which extracellular ATP raises intracellular ATP is not fully resolved
    • Single lab
  9. 2015 Medium

    Established that excess TNAP is sufficient to drive pathologic mineralization in vascular cells via PPi hydrolysis and downstream BMP-2 induction.

    Evidence TNAP overexpression and exogenous AP in VSMCs with noggin rescue, plus endothelial Tie2-Cre transgenic overexpression causing arterial calcification

    PMID:26675253 PMID:27932058

    Open questions at the time
    • How PPi depletion mechanistically activates BMP-2/osteochondrogenic transcription is incomplete
    • Gain-of-function models may not reflect endogenous regulation
  10. 2016 High

    Positioned TNAP in disease-associated ectopic calcification, showing compensatory TNAP upregulation in CD73-deficient cells depletes PPi and activates AKT/mTOR signaling.

    Evidence ACDC patient iMSCs with TNAP activity/PPi assays and in vivo teratoma model; CD73-inhibition cardiomyocyte epistasis

    PMID:24894822 PMID:27965423

    Open questions at the time
    • The signal linking PPi/adenosine changes to AKT/mTOR is correlative
    • Generality across calcification disorders not established
  11. 2019 High

    Implicated TNAP in HLA-B27-driven pathologic bone formation, defining an sXBP1/RARB/TNAP axis driving Runx2-independent mineralization.

    Evidence Ankylosing spondylitis patient MSCs with mineralization assays, in vivo implantation, and TNAP inhibitor treatment

    PMID:31682238

    Open questions at the time
    • How TNAP bypasses Runx2 is not mechanistically resolved
  12. 2019 Medium

    Revealed a non-mineralization signaling role, showing TNAP physically interacts with and limits SMAD2/3 phosphorylation to restrain TGF-β fibrotic signaling.

    Evidence Co-localization, TNAP overexpression/inhibition, and SMAD2/3 phosphorylation assays in cardiac/skeletal muscle

    PMID:31289197

    Open questions at the time
    • Direct dephosphorylation of SMAD2/3 by TNAP not biochemically demonstrated
    • Cardiac fibrosis studies report opposing TNAP directionality, leaving net role context-dependent
  13. 2021 Medium

    Reported conflicting roles for TNAP in cardiac fibrosis, with one study placing inhibition as antifibrotic (via p53) and another showing knockdown ameliorates fibrosis through TGF-β1/Smads/ERK.

    Evidence Pharmacological inhibition and bidirectional adenoviral knockdown/overexpression in MI models and cardiac fibroblasts

    PMID:31969558 PMID:33971401

    Open questions at the time
    • The directionality of TNAP's effect on fibrosis is unreconciled across models
    • Substrate responsible for the signaling effect is unidentified
  14. 2021 High

    Uncovered a non-canonical mitochondrial, thermogenic role, showing adipocyte TNAP hydrolyzes phosphocreatine to power a futile creatine cycle controlling energy expenditure.

    Evidence Mitochondrial phosphocreatine phosphatase assays, subcellular fractionation, and adipocyte-specific knockout with obesity phenotype

    PMID:33981039

    Open questions at the time
    • Mechanism targeting TNAP to mitochondria rather than the plasma membrane is unknown
    • How a GPI-anchored ectoenzyme accesses phosphocreatine is unresolved
  15. 2022 Medium

    Placed TNAP downstream of adrenergic signaling, showing ADRA1A-Gαq cooperates with β3-AR to induce and require TNAP for thermogenesis.

    Evidence In vivo genetic epistasis combining Gαq and Gαs signaling models with TNAP loss-of-function

    PMID:36344764

    Open questions at the time
    • Direct transcriptional regulators linking adrenergic input to TNAP induction not defined
  16. 2022 Medium

    Defined a neurodegenerative substrate, showing TNAP dephosphorylates extracellular tau to create an M1/M3 muscarinic agonist that drives neuronal death in tauopathy.

    Evidence TNAP haploinsufficiency and pharmacological inhibition in P301S mice with behavioral, pathological, and human-brain protein analyses

    PMID:35065251

    Open questions at the time
    • Direct enzymatic dephosphorylation sites on tau not mapped
    • Relevance to sporadic human tauopathy beyond protein-level association unproven
  17. 2018 Medium

    Connected TNAP to brain extracellular ATP homeostasis and excitability, linking haploinsufficiency to lower CSF ATP, reduced Pannexin-1, and seizure susceptibility, complementing roles at synaptic clefts/nodes of Ranvier and in myelination.

    Evidence TNAP+/- mice with CSF ATP measurement and seizure assays; histochemical synaptic localization; Akp2-/- ultrastructure and brain metabolomics

    PMID:22696173 PMID:26219708 PMID:28072448 PMID:29551976

    Open questions at the time
    • Causal chain from ATP hydrolysis to Panx1 regulation is unresolved
    • Specific substrates governing neurotransmitter levels not pinned down
  18. 2025 Medium

    Identified a moonlighting receptor function, showing ALPL on brain vascular endothelium directly binds and mediates transcytosis of an engineered AAV across the blood-brain barrier.

    Evidence AAV capsid evolution, direct ALPL binding assays, cell barrier transcytosis model, and in vivo rodent/primate transduction

    PMID:40340250

    Open questions at the time
    • Endogenous transcytosis ligand/cargo for ALPL not identified
    • Whether catalytic activity is involved in transcytosis is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single GPI-anchored ectoenzyme is targeted to distinct compartments (plasma membrane, synaptic clefts, mitochondria) and how its substrate selection is tuned in each context to produce its divergent skeletal, metabolic, neural, and fibrotic outputs.
  • No structural model linking metalation, lipid microenvironment, and catalytic state
  • Mechanism of mitochondrial targeting unknown
  • Direct protein substrates (SMAD2/3, tau) not biochemically validated as TNAP substrates in all cases

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140096 catalytic activity, acting on a protein 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 2
Partners
DHX36HDAC1HDAC4SMAD2ZNT5ZNT7

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 TNAP is the primary enzyme that hydrolyzes both ATP and PPi in the matrix vesicle (MV) compartment during endochondral bone formation; loss of TNAP had the most pronounced effect on hydrolysis of all physiologic substrates (ATP, ADP, PPi) compared to loss of NPP1 or PHOSPHO1 in osteoblast-derived MVs. Kinetic analysis of substrate hydrolysis by isolated wild-type vs. TNAP-, NPP1-, and PHOSPHO1-deficient matrix vesicles Journal of bone and mineral research High 19874193
2021 In thermogenic adipocytes, TNAP is localized to mitochondria (not plasma membrane as in other cells) and functions as a phosphocreatine phosphatase, hydrolyzing phosphocreatine to initiate a futile creatine cycle that dissipates energy as heat. Genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and causes rapid-onset obesity in mice. Biochemical phosphocreatine phosphatase assays in isolated mitochondria, TNAP inhibitor experiments in isolated mitochondria, adipocyte-specific genetic ablation (knockout) with whole-body energy expenditure measurement and obesity phenotype readout, subcellular fractionation/localization Nature High 33981039
2022 ADRA1A-Gαq signaling in adipocytes promotes thermogenesis through a pathway that requires TNAP (and creatine kinase B) as effector proteins of the futile creatine cycle; coordinated α1-AR and β3-AR signaling induces thermogenic gene expression including TNAP. Genetic epistasis in vivo (combined Gαq and Gαs signaling mouse models), TNAP loss-of-function, gene expression analysis Nature metabolism Medium 36344764
2016 In ACDC (CD73-deficient) patient-derived iMSCs, increased TNAP activity depletes PPi (a mineralization inhibitor) and generates adenosine, contributing to ectopic calcification via activation of AKT/mTOR/p70S6K signaling. TNAP activity increased in patient cells compensating for loss of CD73-mediated adenosine production. iPSC-derived mesenchymal stromal cell cultures from ACDC patients, TNAP activity assays, PPi measurement, AKT/mTOR/p70S6K pathway analysis, in vivo teratoma model with pharmacological interventions Science signaling High 27965423
2019 HLA-B27 activates a sXBP1/RARB/TNAP axis in mesenchymal stem cells from ankylosing spondylitis patients, leading to TNAP-mediated accelerated mineralization and syndesmophyte formation independently of Runx2. TNAP inhibitors (levamisole, pamidronate) blocked bony appositions in vivo. AS patient MSC cultures, in vitro mineralization assays, animal model (AS MSC implantation into NOD-SCID mice), TNAP inhibitor treatment in vitro and in vivo, pathway analysis The Journal of clinical investigation High 31682238
2013 Full activation of TNAP in the early secretory pathway requires cooperative cytoplasmic zinc handling by ZnT1, metallothionein (MT), and ZnT4; loss of all three markedly reduces TNAP activity despite increased cytosolic zinc, indicating the cytoplasmic zinc supply pathway is distinct from direct zinc loading by ZnT5-ZnT6/ZnT7 complexes. Gene disruption of ZnT1, MT, and ZnT4 (triple KO cells), re-expression of wild-type and zinc transport-incompetent mutants, TNAP activity assay PloS one High 24204829
2016 The di-proline (PP) motif in luminal loop 2 of ZnT5 and ZnT7 is required for TNAP activation in the early secretory pathway; PP-to-AA mutation almost completely abolished TNAP activation without impairing zinc transport activity, demonstrating the PP-motif participates in TNAP maturation/metalation rather than zinc transport per se. Triple KO cells lacking ZnT5-ZnT6 and ZnT7, re-expression of PP-AA point mutants, TNAP activity assay, zinc supplementation rescue experiments The Biochemical journal High 27303047
2015 TNAP and PHOSPHO1 play non-redundant cooperative roles in initiating skeletal mineralization; simultaneous inhibition of both enzymes essentially abolishes matrix mineralization (85%), whereas individual inhibition only partially reduces it, indicating critical functional crosstalk in osteoblast/chondrocyte mineralization. Osteoblast cell culture (MC3T3-E1 clones), lentiviral PHOSPHO1 overexpression, specific PHOSPHO1 and TNAP inhibitors alone and in combination, ex vivo metatarsal culture, mineralization assays Biochemistry and biophysics reports Medium 26457330
2019 TNAP colocalizes and physically interacts with SMAD2, and TNAP overexpression reduces SMAD2/3 phosphorylation and downstream fibrotic gene expression, while TNAP inhibition increases SMAD2/3 phosphorylation; this defines TNAP as a negative regulator of TGF-β/SMAD2/3 signaling and a limiter of fibrosis in cardiac and skeletal muscle. Co-localization by immunofluorescence, TNAP overexpression/inhibition in cardiac and skeletal muscle cells/tissue, SMAD2/3 phosphorylation assays, fibrotic gene expression analysis Journal of cell science Medium 31289197
2020 TNAP inhibition attenuates cardiac fibrosis after myocardial infarction by suppressing TGF-β1/Smads signaling and upregulating p53; the antifibrotic effect of TNAP inhibition was blocked by a p53 inhibitor, placing TNAP upstream of both TGF-β1/Smads and p53 in cardiac fibroblast differentiation. TNAP inhibitor (tetramisole) in rat MI model, primary cardiac fibroblast cultures, migration/differentiation assays, signaling pathway analysis, p53 inhibitor rescue experiment Cell death & disease Medium 31969558
2021 TNAP promotes cardiac fibrosis after myocardial infarction by activating TGF-β1/Smads and ERK1/2 signaling; adenovirus-mediated TNAP knockdown ameliorated fibrosis and improved cardiac function, while TNAP overexpression aggravated fibrosis in mice. Adenovirus-mediated knockdown and overexpression in vivo (mouse MI model) and in vitro (cardiac fibroblasts), TGF-β1/Smads and ERK1/2 pathway analysis EBioMedicine Medium 33971401
2011 TNAP transcription is regulated by the HDAC1/4-Dhx36 axis: Dhx36 binds the TNAP promoter at an MS-275 response element and drives TNAP transcription; HDAC1 and HDAC4 interact with Dhx36 and suppress TNAP transcription by a deacetylase-independent mechanism, which is relieved by the HDAC inhibitor MS-275. TNAP promoter deletion constructs/luciferase assay, DNA affinity precipitation assay (Dhx36 identification), co-immunoprecipitation (Dhx36 interaction with HDAC1/4), forced expression of HDACs Journal of bone and mineral research Medium 21590736
2018 Alpl deficiency in mesenchymal stem cells (MSCs) enhances ATP release and reduces ATP hydrolysis, leading to elevated extracellular ATP that is internalized, raising intracellular ATP and inactivating the AMPKα pathway, causing a cell fate switch toward senescence and adipogenic differentiation at the expense of osteogenic differentiation. Alpl KO/knockdown in MSCs, extracellular and intracellular ATP measurements, AMPKα pathway analysis, pharmacological reactivation with metformin in Alpl+/- mice, bone phenotype analysis Bone research Medium 30210899
2012 TNAP deficiency (Akp2 knockout) causes decreased myelinated axons and white matter in the spinal cord and absent myelinated cortical axons, along with an increased proportion of immature cortical synapses, demonstrating that TNAP is required for normal myelination and synaptogenesis in the developing brain. TNAP knockout mice (Akp2-/-), light and electron microscopy of spinal cord and cerebral cortex during postnatal development Cell and tissue research Medium 22696173
2004 NOTE: This paper (PMID 15208311) describes a protein called 'TNAP' (TRAFs and NIK-associated protein) that is a repressor of NF-κB-inducing kinase (NIK) — this is a DIFFERENT protein from tissue-nonspecific alkaline phosphatase (ALPL/TNAP). This is an alias collision and is excluded. N/A — alias collision The Journal of biological chemistry Low 15208311
2015 TNAP overexpression in vascular smooth muscle cells (VSMCs) or addition of exogenous alkaline phosphatase is sufficient to induce VSMC trans-differentiation into chondrocyte-like cells and mineralization; this effect is mediated through PPi hydrolysis leading to calcium phosphate crystal deposition, which in turn activates BMP-2 expression; noggin (BMP-2 inhibitor) blocked the chondrogenic response. TNAP overexpression in VSMC lines (MOVAS, A7R5), exogenous AP addition, TNAP inhibition in primary chondrocytes, BMP-2 inhibitor (noggin) rescue experiment, chondrocyte marker expression analysis Biochimica et biophysica acta. Molecular basis of disease Medium 27932058
2014 CD73-derived adenosine suppresses TNAP activity in cardiomyocytes; loss of CD73 activity (pharmacological inhibition) directly induced hypertrophy and calcification in the absence of phenylephrine, and these responses were abrogated by TNAP inhibition, placing TNAP downstream of CD73/adenosine in cardiomyocyte calcification and hypertrophy. Neonatal rat cardiomyocyte cultures, CD73 inhibitor (α,β-methylene ADP), TNAP inhibitor (tetramisole), adenosine analog treatment, Alizarin Red S staining for calcification, ANP gene expression for hypertrophy Molecular and cellular biochemistry Medium 24894822
2015 TNAP expression is regulated by sensory input in the primate cerebral cortex; TNAP is specifically localized to synaptic clefts and nodes of Ranvier, and exhibits high activity in layer 4 of sensory cortices, suggesting TNAP plays a role in modulating synaptic transmission through nucleotide hydrolysis at these specialized subcellular compartments. Histochemical activity assays, immunolocalization, activity measurement in sensory deprivation/manipulation paradigms in primate cortex Sub-cellular biochemistry Medium 26219708
2015 TNAP promotes axonal growth by hydrolyzing extracellular ATP at the axonal growth cone, thereby preventing P2X7 receptor-mediated inhibition of axonal elongation; a reciprocal regulatory relationship exists between TNAP and P2X7R whereby each can control expression of the other. TNAP overexpression/inhibition in neuronal cultures, ATP hydrolysis assays, P2X7R manipulation, axonal length measurement Sub-cellular biochemistry Low 26219721
2022 TNAP dephosphorylates extracellular hyperphosphorylated tau protein; dephosphorylated tau acts as an agonist of muscarinic M1 and M3 receptors, triggering calcium-dependent neuronal death; TNAP haploinsufficiency or pharmacological TNAP inhibition in P301S tauopathy mice reduced eTau dephosphorylation, decreased neuronal hyperactivity and brain atrophy, and increased life expectancy. TNAP haploinsufficiency in P301S mice, pharmacological TNAP inhibition in vivo, behavioral testing (anxiety, motor, memory), brain atrophy measurement, hippocampal neuronal death quantification, TNAP protein level analysis in AD and Pick's disease brain Neurobiology of disease Medium 35065251
2017 TNAP deficiency in the brain alters multiple metabolite levels including GABA, adenosine, cystathionine, and NAA; the most strongly altered metabolites (cystathionine and adenosine) implicate TNAP in regulation of ectonucleotide levels and pyridoxal phosphate-dependent enzyme activities in neural tissue. 1H- and 31P-NMR metabolomics of brain extracts from Akp2-/- knockout mice vs. controls (untargeted analysis of 39 metabolites) Journal of neurochemistry Medium 28072448
2018 Haploinsufficient TNAP+/- mice have lower extracellular ATP levels in cerebrospinal fluid and decreased Pannexin-1 (Panx1) expression in the brain compared to controls, and are more susceptible to ATP-induced seizures; this suggests TNAP participates in maintaining extracellular ATP homeostasis partly through regulating Panx1 expression. TNAP+/- heterozygous mice, CSF ATP measurement, seizure susceptibility assay, Pannexin-1/connexin/ectonucleotidase expression analysis Frontiers in pharmacology Medium 29551976
2015 In the cementum developmental sequence, early TNAP expression creates a low-PPi environment promoting acellular cementum initiation; loss of TNAP in Alpl null mice inhibits acellular cementum formation while increasing (hypomineralized) cellular cementum production, demonstrating a specific role for TNAP-mediated PPi hydrolysis in acellular cementum mineralization. Alpl null and Enpp1 null mouse analysis, histology, immunohistochemistry, in vitro cementoblast cultures with gene/protein expression analysis International journal of oral science Medium 25504209
2015 TNAP overexpression in endothelial cells (driven by Tie2-Cre) is sufficient to induce generalized arterial calcification and upregulate osteochondrogenic genes (Runx2, Bglap, Spp1, Opg, Col2a1) in the aorta, demonstrating the osteogenic potential of TNAP-positive endothelial cells in promoting vascular calcification. Conditional transgenic overexpression of ALPL in endothelial cells (Tie2-Cre), vascular calcium quantification, osteochondrogenic gene expression, blood pressure measurement, cardiac phenotyping Journal of the American Heart Association Medium 26675253
2014 TNAP deficiency in Alpl-/- calvarial cells promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis, and increased cell adhesion; in vivo, Alpl-/- mice develop craniosynostosis with bony coronal suture fusion, demonstrating a cell-autonomous role for TNAP in calvarial cell behavior and craniofacial development. Alpl-/- mouse model, micro-CT and histology of craniofacial bones, TNAP shRNA knockdown in MC3T3E1(C4) calvarial cells, mineralization assays, gene expression, proliferation/apoptosis/cell adhesion assays Bone Medium 25014884
2017 TNAP is required for normal cranial base growth and hypertrophic chondrocyte maturation/apoptosis; Alpl-/- primary rib chondrocytes exhibit diminished MAPK signaling, reduced chondrocyte apoptosis, and aberrant gene expression; mineral-targeted recombinant TNAP rescue normalized the cranial base phenotype, placing TNAP upstream of MAPK in chondrocyte maturation. Alpl-/- mouse micro-CT and histomorphometry, primary rib chondrocyte cultures, MAPK signaling analysis, recombinant TNAP (strensiq) rescue experiment Frontiers in physiology Medium 28377728
2008 Androgen/androgen receptor (AR) signaling upregulates TNAP expression and activity in osteoblasts to promote bone formation and mineralization; ectopic TNAP expression or inorganic phosphate partially rescues the mineralization defect caused by AR deficiency; TNAP and SIBLING family genes are androgen target genes in osteoblasts. AR-deficient mouse calvaria analysis, enforced AR expression and AR knockdown in osteoblasts, TNAP activity and expression assays, ectopic TNAP expression rescue experiments Molecular and cellular biology Medium 18838539
2025 ALPL serves as the primary receptor mediating receptor-mediated transcytosis of engineered AAV vector VCAP-102 across the blood-brain barrier; direct binding of VCAP-102 to human ALPL was demonstrated, and ALPL is expressed on brain vascular endothelial cells where it enables CNS delivery. AAV capsid evolution platform (TRACER), identification of ALPL as primary receptor by binding assays, cell barrier transcytosis model with ALPL, in vivo rodent and primate brain transduction Molecular therapy Medium 40340250
2012 TNAP is overexpressed in bovine brain capillary endothelial cells after re-induction of blood-brain barrier properties, suggesting TNAP expression is upregulated as part of the BBB phenotype establishment. Differential nano-LC MALDI-TOF/TOF-MS proteomics of BBB vs. non-BBB bovine brain capillary endothelial cells, biochemical validation PloS one Low 23119012
2015 GPI-anchored TNAP increases lipid dynamics and decreases ordering throughout the bilayer of DPPC proteoliposomes, with the largest effect in the core acyl chain region, indicating that TNAP membrane anchoring induces long-range modifications in membrane fluidity that could influence membrane-associated processes. Electron Spin Resonance (ESR) with spin-labeled phospholipids in DPPC liposomes and TNAP-containing proteoliposomes, non-linear least-squares simulations Physical chemistry chemical physics Low 26389140
2020 TNAP catalytic activity and mineral propagation efficiency in proteoliposomes is modulated by membrane lipid composition; proteoliposomes containing sphingomyelin showed highest membrane organization, highest TNAP ATP hydrolysis efficiency, and most efficient amorphous calcium phosphate precipitation, demonstrating that the lipid microenvironment regulates TNAP function in matrix vesicle-mediated biomineralization. TNAP-harboring proteoliposomes with varying lipid compositions (DMPC, with/without cholesterol and sphingomyelin), calorimetry, turbidimetry, FTIR spectroscopy, ATP hydrolysis kinetics Archives of biochemistry and biophysics Low 32710882
2019 ALPL overexpression in high-grade serous ovarian cancer cells inhibits migration, invasion, and EMT by reducing expression of WNT5A, its receptor FZD2, and downstream phospho-STAT3; knockdown of FZD2 mimicked ALPL overexpression and recombinant WNT5A reversed the ALPL overexpression effects, placing ALPL upstream of the WNT5A-FZD2-STAT3 non-canonical WNT axis. ALPL overexpression in SKOV3 and HEY cell lines, migration/invasion assays, FZD2 siRNA knockdown, recombinant WNT5A rescue, gene ontology analysis, TCGA database correlation Biochemical and biophysical research communications Low 30979497

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Kinetic analysis of substrate utilization by native and TNAP-, NPP1-, or PHOSPHO1-deficient matrix vesicles. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 111 19874193
2021 Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine. Nature 107 33981039
2023 Immunosuppressive CD10+ALPL+ neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells. Journal of hepatology 101 37689322
1993 A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Genomics 100 8406453
1998 Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia. European journal of human genetics : EJHG 97 9781036
2009 Discovery and validation of a series of aryl sulfonamides as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP). Journal of medicinal chemistry 85 19821572
2014 Tissue-nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the Alpl(-/-) mouse model of infantile hypophosphatasia. Bone 82 25014884
2015 Transgenic Overexpression of Tissue-Nonspecific Alkaline Phosphatase (TNAP) in Vascular Endothelium Results in Generalized Arterial Calcification. Journal of the American Heart Association 76 26675253
2016 Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC. Science signaling 73 27965423
2019 Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis. Circulation. Genomic and precision medicine 71 32141789
2018 Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells. Bone research 71 30210899
2010 Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers. Journal of human genetics 64 21179104
2020 TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways. Cell death & disease 61 31969558
2019 HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. The Journal of clinical investigation 55 31682238
2022 TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body. Cardiovascular research 53 33070177
2015 Counter-regulatory phosphatases TNAP and NPP1 temporally regulate tooth root cementogenesis. International journal of oral science 53 25504209
2022 ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP. Nature metabolism 52 36344764
2016 Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia. Journal of dental research 51 27582029
2023 The Global ALPL gene variant classification project: Dedicated to deciphering variants. Bone 50 37898381
2011 Histone deacetylase inhibitor MS-275 stimulates bone formation in part by enhancing Dhx36-mediated TNAP transcription. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 46 21590736
2014 Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl-/- mice by administration of soluble (non-targeted) chimeric alkaline phosphatase. Bone 45 25433339
2012 Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain. Cell and tissue research 45 22696173
2000 Fifteen new mutations (-195C>T, L-12X, 298-2A>G, T117N, A159T, R229S, 997+2T>A, E274X, A331T, H364R, D389G, 1256delC, R433H, N461I, C472S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with hypophosphatasia. Human mutation 44 10679946
2017 Genetic analysis of adults heterozygous for ALPL mutations. Journal of bone and mineral metabolism 43 29236161
2016 TNAP stimulates vascular smooth muscle cell trans-differentiation into chondrocytes through calcium deposition and BMP-2 activation: Possible implication in atherosclerotic plaque stability. Biochimica et biophysica acta. Molecular basis of disease 43 27932058
2017 Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR-based metabolomics analysis. Journal of neurochemistry 38 28072448
2017 Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. American journal of medical genetics. Part A 38 28127875
2021 TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-β/Smads and ERK1/2 signaling pathways. EBioMedicine 37 33971401
2019 Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients. Calcified tissue international 36 31707452
1999 Differential expression and activity of tissue-nonspecific alkaline phosphatase (TNAP) in rat odontogenic cells in vivo. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 36 10567438
2017 Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor. Bioorganic & medicinal chemistry letters 35 29174347
2019 Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene. Scientific reports 34 31267001
2012 Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 21956185
2023 ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma. Nature communications 33 37291203
2020 Loss-of-Function Mutations in the ALPL Gene Presenting with Adult Onset Osteoporosis and Low Serum Concentrations of Total Alkaline Phosphatase. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 33 31793067
2013 Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia. Bone 33 23454488
1999 Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online. Human mutation 33 10094560
2020 Circular RNA SIPA1L1 regulates osteoblastic differentiation of stem cells from apical papilla via miR-204-5p/ALPL pathway. Stem cell research & therapy 32 33138854
2017 Topographic analysis by atomic force microscopy of proteoliposomes matrix vesicle mimetics harboring TNAP and AnxA5. Biochimica et biophysica acta. Biomembranes 31 28549727
2013 Cooperative functions of ZnT1, metallothionein and ZnT4 in the cytoplasm are required for full activation of TNAP in the early secretory pathway. PloS one 31 24204829
2011 MSCA-1/TNAP selection of human jaw periosteal cells improves their mineralization capacity. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 21220938
2006 Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry. The Journal of pediatrics 30 16769381
2004 TNAP, a novel repressor of NF-kappaB-inducing kinase, suppresses NF-kappaB activation. The Journal of biological chemistry 29 15208311
2015 The Functional co-operativity of Tissue-Nonspecific Alkaline Phosphatase (TNAP) and PHOSPHO1 during initiation of Skeletal Mineralization. Biochemistry and biophysics reports 28 26457330
2002 Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients. European journal of human genetics : EJHG 28 12357339
2025 Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier. Molecular therapy : the journal of the American Society of Gene Therapy 27 40340250
2021 Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D10 Improves the Skeletal and Dentoalveolar Phenotypes in Alpl-/- Mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 27 34076297
2007 Association of a TNAP haplotype with ankylosing spondylitis. Arthritis and rheumatism 27 17195227
2020 Genotype-Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia. Calcified tissue international 25 33191482
2018 Incidence of Mutations in the ALPL, GGPS1, and CYP1A1 Genes in Patients With Atypical Femoral Fractures. JBMR plus 25 30680361
2012 TNAP and EHD1 are over-expressed in bovine brain capillary endothelial cells after the re-induction of blood-brain barrier properties. PloS one 25 23119012
2020 Dental defects in the primary dentition associated with hypophosphatasia from biallelic ALPL mutations. Bone 24 33160095
2017 Tissue Nonspecific Alkaline Phosphatase (TNAP) Regulates Cranial Base Growth and Synchondrosis Maturation. Frontiers in physiology 24 28377728
2021 TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism. International journal of molecular sciences 23 33477631
2020 Pharmacological TNAP inhibition efficiently inhibits arterial media calcification in a warfarin rat model but deserves careful consideration of potential physiological bone formation/mineralization impairment. Bone 23 32360899
2003 Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene. Human mutation 23 12815606
2021 TNAP: A New Multitask Enzyme in Energy Metabolism. International journal of molecular sciences 22 34638808
2019 The rs1256328 (ALPL) and rs12654812 (RGS14) Polymorphisms are Associated with Susceptibility to Calcium Nephrolithiasis in a Taiwanese population. Scientific reports 22 31754202
2015 Rediscovering TNAP in the Brain: A Major Role in Regulating the Function and Development of the Cerebral Cortex. Sub-cellular biochemistry 22 26219708
2013 Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype. Bone 22 23791648
2006 Characterization of missense mutations and large deletions in the ALPL gene by sequencing and quantitative multiplex PCR of short fragments. Genetic testing 22 17253930
1993 Linkage relationships between ALPL, ENO1, GPI, PGD, and TGFB1 on porcine chromosome 6. Genomics 22 8104872
2016 The PP-motif in luminal loop 2 of ZnT transporters plays a pivotal role in TNAP activation. The Biochemical journal 21 27303047
2015 Multiple Functions of MSCA-1/TNAP in Adult Mesenchymal Progenitor/Stromal Cells. Stem cells international 21 26839555
2014 CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation. Molecular and cellular biochemistry 21 24894822
2008 Altered TNSALP expression and phosphate regulation contribute to reduced mineralization in mice lacking androgen receptor. Molecular and cellular biology 21 18838539
2005 FGF2 alters expression of the pyrophosphate/phosphate regulating proteins, PC-1, ANK and TNAP, in the calvarial osteoblastic cell line, MC3T3E1(C4). Connective tissue research 21 16546821
2001 Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. American journal of medical genetics 21 11745997
2013 Characterization of six missense mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in Chinese children with hypophosphatasia. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 24022022
2019 ALPL regulates the aggressive potential of high grade serous ovarian cancer cells via a non-canonical WNT pathway. Biochemical and biophysical research communications 18 30979497
2019 TNAP limits TGF-β-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2/3 transcription factors. Journal of cell science 18 31289197
2018 lncRNA HOTAIR Inhibits Mineralization in Osteoblastic Osteosarcoma Cells by Epigenetically Repressing ALPL. Calcified tissue international 18 29846771
2016 A homozygous intronic branch-point deletion in the ALPL gene causes infantile hypophosphatasia. Bone 18 27777120
2009 Association of ALPL and ENPP1 gene polymorphisms with bone strength related skeletal traits in a Chuvashian population. Bone 18 19931660
2022 Gene Therapy Using Recombinant AAV Type 8 Vector Encoding TNAP-D10 Improves the Skeletal Phenotypes in Murine Models of Osteomalacia. JBMR plus 17 36699639
2019 Cloning, Purification, and Characterization of Recombinant Thermostable β-Xylanase Tnap_0700 from Thermotoga naphthophila. Applied biochemistry and biotechnology 17 31240547
2015 Effects of GPI-anchored TNAP on the dynamic structure of model membranes. Physical chemistry chemical physics : PCCP 17 26389140
2020 Lipid composition modulates ATP hydrolysis and calcium phosphate mineral propagation by TNAP-harboring proteoliposomes. Archives of biochemistry and biophysics 15 32710882
2018 Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels. Frontiers in pharmacology 15 29551976
2010 Do cytokines induce vascular calcification by the mere stimulation of TNAP activity? Medical hypotheses 15 20674184
2019 Loss of tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels is coupled to persistent neuroinflammation and behavioral deficits in late sepsis. Brain, behavior, and immunity 14 31778743
2018 Four novel mutations in the ALPL gene in Chinese patients with odonto, childhood, and adult hypophosphatasia. Bioscience reports 14 29724887
2018 A case of perinatal hypophosphatasia with a novel mutation in the ALPL gene: clinical course and review of the literature. Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 14 30083035
2017 Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with hypochondroplasia and hypophosphatasia. American journal of medical genetics. Part A 14 28763161
2024 New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry. American journal of medical genetics. Part A 13 38884565
2019 Genetic correction of induced pluripotent stem cells mediated by transcription activator-like effector nucleases targeting ALPL recovers enzyme activity and calcification in vitro. Molecular genetics and metabolism 13 31178256
2018 The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitamer Levels in CSF and Plasma. Genes 13 30583557
2015 TNAP Plays a Key Role in Neural Differentiation as well as in Neurodegenerative Disorders. Sub-cellular biochemistry 13 26219721
2011 Novel heterozygous tissue-nonspecific alkaline phosphatase (TNAP) gene mutations causing lethal perinatal hypophosphatasia. Journal of bone and mineral metabolism 13 21638016
2023 TNAP and P2X7R: New Plasma Biomarkers for Alzheimer's Disease. International journal of molecular sciences 12 37446074
2022 Apigenin Modulates AnxA6- and TNAP-Mediated Osteoblast Mineralization. International journal of molecular sciences 12 36361965
2020 Synthesis, characterization, in vitro tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP) inhibition studies and computational evaluation of novel thiazole derivatives. Bioorganic chemistry 12 32711087
2020 Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development. Scientific reports 12 32770041
2016 Pyridoxine-Responsive Seizures in Infantile Hypophosphatasia and a Novel Homozygous Mutation in ALPL Gene. Journal of clinical research in pediatric endocrinology 12 27086862
2016 The Expression of PHOSPHO1, nSMase2 and TNAP is Coordinately Regulated by Continuous PTH Exposure in Mineralising Osteoblast Cultures. Calcified tissue international 12 27444010
2007 A case of lethal hypophosphatasia providing new insights into the perinatal benign form of hypophosphatasia and expression of the ALPL gene. Clinical genetics 12 17922851
2022 TNAP-a potential cytokine in the cerebral inflammation in spastic cerebral palsy. Frontiers in molecular neuroscience 11 36187348
2022 TNAP upregulation is a critical factor in Tauopathies and its blockade ameliorates neurotoxicity and increases life-expectancy. Neurobiology of disease 10 35065251
2019 Two novel mutations in the ALPL gene of unrelated Chinese children with Hypophosphatasia: case reports and literature review. BMC pediatrics 10 31760938
2018 Common Variants in ALPL Gene Contribute to the Risk of Kidney Stones in the Han Chinese Population. Genetic testing and molecular biomarkers 10 29489416

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