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Journal of Bone and Mineral Research :... Feb 2018Alkaline phosphatase can be considered "our favorite enzyme" for reasons apparent to those who diagnose and treat metabolic bone diseases or who study skeletal biology....
Alkaline phosphatase can be considered "our favorite enzyme" for reasons apparent to those who diagnose and treat metabolic bone diseases or who study skeletal biology. Few might know, however, that alkaline phosphatase likely represents the most frequently assayed enzyme in all of medicine. Elevated activity in the circulation is universally recognized as a marker for skeletal or hepatobiliary disease. Nevertheless, the assay conditions in many ways are nonphysiological. The term alkaline phosphatase emerged when it became necessary to distinguish "bone phosphatase" from the phosphatase in the prostate that features an acidic pH optimum. Beginning in 1948, studies of the inborn-error-of-metabolism hypophosphatasia would identify the natural substrates and establish the physiological role of alkaline phosphatase, including in biomineralization. Here, we recount the discovery in 1923 and then eventual naming of this enzyme that remains paramount in our field. © 2017 American Society for Bone and Mineral Research.
Topics: Alkaline Phosphatase; Enzyme Assays; History, 20th Century; Humans; Terminology as Topic
PubMed: 28727174
DOI: 10.1002/jbmr.3225 -
Human Mutation Jul 2020Hypophosphatasia (HPP) is a rare metabolic disorder characterized by low tissue-nonspecific alkaline phosphatase (TNSALP) typically caused by ALPL gene mutations. HPP is...
Hypophosphatasia (HPP) is a rare metabolic disorder characterized by low tissue-nonspecific alkaline phosphatase (TNSALP) typically caused by ALPL gene mutations. HPP is heterogeneous, with clinical presentation correlating with residual TNSALP activity and/or dominant-negative effects (DNE). We measured residual activity and DNE for 155 ALPL variants by transient transfection and TNSALP enzymatic activity measurement. Ninety variants showed low residual activity and 24 showed DNE. These results encompass all missense variants with carrier frequencies above 1/25,000 from the Genome Aggregation Database. We used resulting data as a reference to develop a new computational algorithm that scores ALPL missense variants and predicts high/low TNSALP enzymatic activity. Our approach measures the effects of amino acid changes on TNSALP dimer stability with a physics-based implicit solvent energy model. We predict mutation deleteriousness with high specificity, achieving a true-positive rate of 0.63 with false-positive rate of 0, with an area under receiver operating curve (AUC) of 0.9, better than all in silico predictors tested. Combining this algorithm with other in silico approaches can further increase performance, reaching an AUC of 0.94. This study expands our understanding of HPP heterogeneity and genotype/phenotype relationships with the aim of improving clinical ALPL variant interpretation.
Topics: Alkaline Phosphatase; Humans; Hypophosphatasia; Mutation, Missense; Protein Structure, Tertiary
PubMed: 32160374
DOI: 10.1002/humu.24010 -
Calcified Tissue International Apr 2016Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular... (Review)
Review
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 features rickets or osteomalacia and hypomineralization of teeth. Enzyme replacement using mineral-targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life-threatening HPP. Clinical trials are revealing aspects of HPP pathophysiology not yet fully understood, such as craniosynostosis and muscle weakness when HPP is severe. New treatment approaches are under development to improve patient care.
Topics: Alkaline Phosphatase; Animals; Humans; Hypophosphatasia; Mice
PubMed: 26590809
DOI: 10.1007/s00223-015-0079-1 -
Cancer Research Oct 2020Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In...
Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In mesothelioma, we identified a highly specific tumor cell surface antigen that can be targeted for therapy development. Mesothelioma is caused by malignant transformation of the mesothelium, is incurable, and can be categorized into three histologic subtypes: epithelioid, biphasic, and sarcomatoid. To identity novel mesothelioma cell surface antigens with broad subtype coverage and high tissue specificity, we have previously selected phage antibody display libraries on live mesothelioma cells and tissues following counterselection on normal cells and identified a panel of human antibodies that bind all subtypes of mesothelioma, but not normal mesothelium. One of the antibodies, M25, showed high specificity against an antigen we identify here as ALPPL2. IHC on normal human tissues found that ALPPL2 is expressed only on placental trophoblasts, but not on any other normal tissues. This significant tissue specificity and broad tumor type coverage suggest that ALPPL2 could be an excellent cell surface target for therapeutic development against mesothelioma. To evaluate therapeutic potential of ALPPL2 targeting, an ALPPL2-targeted antibody-drug conjugate was developed and demonstrated potent and specific tumor killing and against both epithelioid and sarcomatoid mesothelioma. Thus, ALPPL2 belongs to a rare class of cell surface antigens classified as truly tumor specific and is well suited for therapy development against ALPPL2-expressing tumors. SIGNIFICANCE: These findings identify ALPP2 as a true tumor-specific cell surface antigen whose tissue specificity enables the development of novel therapies.
Topics: Alkaline Phosphatase; Animals; Antigens, Surface; Antineoplastic Agents, Immunological; CHO Cells; Cell Line, Tumor; Cricetulus; Epitopes; Female; GPI-Linked Proteins; Humans; Immunoconjugates; Immunoglobulin G; Male; Mesothelioma, Malignant; Mice, Inbred NOD; Molecular Targeted Therapy; Xenograft Model Antitumor Assays
PubMed: 32868383
DOI: 10.1158/0008-5472.CAN-20-1418 -
Archives of Endocrinology and Metabolism May 2023Hypophosphatasia (HPP) is an inherited disease caused by a low activity of tissue-nonspecific alkaline phosphatase, a hydrolase that removes phosphate groups from many... (Review)
Review
Hypophosphatasia (HPP) is an inherited disease caused by a low activity of tissue-nonspecific alkaline phosphatase, a hydrolase that removes phosphate groups from many molecules. Decreased alkaline phosphatase activity leads to the accumulation of three main metabolites, ., pyridoxal 5´-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine. Impairment in PLP dephosphorylation induces seizures, while PPi accumulation inhibits bone mineralization. Clinically, HPP has a wide spectrum of presentations, ranging from neonatal death to an apparent lack of symptoms. This disease is classified into six subtypes according to the age at onset of first signs or symptoms. The clinical manifestations of the disease include rickets-like bone changes, bone demineralization, fragility fractures, reduced muscular strength, chest deformity, pulmonary hypoplasia, nephrolithiasis, nephrocalcinosis, and chondrocalcinosis. Treatment of HPP consists of enzyme replacement therapy. Before this therapy was approved, treatment was palliative and associated with high morbidity and mortality. Asfotase alfa has changed the prognosis of the disease by reducing bone deformity and improving bone mineralization, lung function, and muscle weakness, among other benefits. In adults, teriparatide and anti-sclerostin antibody have been used off-label in selected cases, demonstrating benefit in accelerating fracture healing and in concomitant treatment of osteoporosis. This review summarizes the main aspects of HPP and identifies the particularities of the disease in adult patients.
Topics: Adult; Infant, Newborn; Humans; Alkaline Phosphatase; Hypophosphatasia; Osteoporosis; Enzyme Replacement Therapy
PubMed: 37249457
DOI: 10.20945/2359-3997000000626 -
Cells Jan 2022The experiences of a laboratory which pioneered the application of monoclonal antibodies to diagnostic histochemistry is described. This was achieved in four key steps:... (Review)
Review
The experiences of a laboratory which pioneered the application of monoclonal antibodies to diagnostic histochemistry is described. This was achieved in four key steps: (1) Monoclonal antibodies were successfully produced to replace the difficult-to-produce and limited polyclonal antibodies available for immunohistochemistry. (2) Monoclonal antibodies were produced to improve the immunoenzymatic detection of bound antibodies, using immunoperoxidase or alkaline phosphatase, increasing sensitivity and allowing the use of two chromogens when applied together. The availability of a reliable alkaline phosphatase-based detection allowed the detection of antigens in tissues with high endogenous peroxidase. (3) Methodologies were developed to unmask antigens not detected in routinely processed paraffin-embedded tissue. (4) Synthetic peptides were used as immunising antigens for the direct production of specific molecules of diagnostic interest. This was expanded to include recombinant proteins. Many reacted with fixed tissue and recognised homologous molecules in other species. In addition to these developments, the laboratory promoted the collaboration and training of researchers to spread the expertise of monoclonal production for diagnosis.
Topics: Alkaline Phosphatase; Animals; Antibodies, Monoclonal; Humans; Immunohistochemistry; Paraffin Embedding; Peptides; Peroxidase
PubMed: 35053359
DOI: 10.3390/cells11020243 -
International Journal of Surgery... Aug 2019
Topics: Albumins; Alkaline Phosphatase; Humans; Lung Neoplasms; Prognosis; Propensity Score; Prospective Studies
PubMed: 31336171
DOI: 10.1016/j.ijsu.2019.07.015 -
Clinica Chimica Acta; International... Jun 2018Neuroendocrine tumors (NETs) are uncommon type of cancers, also known as APUD (amine precursor uptake decarboxylation) tumors, which are becoming increasingly prevalent....
BACKGROUND
Neuroendocrine tumors (NETs) are uncommon type of cancers, also known as APUD (amine precursor uptake decarboxylation) tumors, which are becoming increasingly prevalent. Alkaline phosphatase (ALP) is a poor prognosis factor in a number of hepatic diseases. However, its distribution and prognostic value in primary hepatic neuroendocrine tumors (PHNETs) are still not clear. In this study, our aim is to investigate the correlations between ALP and clinicopathological features and prognostic factors of PHNETs.
METHODS
The clinical data of 22 patients with PHNETs were retrospectively reviewed to investigate whether ALP affects the prognosis of PHNETs.
RESULTS
In this study, ALP is correlated to γ-glutamyl transpeptidase (GGT; p = 0.002) and the tumor location in the liver (p = 0.007), and increased levels of ALP had poor effects on overall survival (p = 0.006) and progression-free survival (p = 0.022).
CONCLUSION
ALP was identified as an independent prognostic factor for overall survival of PHNETs.
Topics: Alkaline Phosphatase; Female; Humans; Male; Neuroendocrine Tumors; Survival Analysis; gamma-Glutamyltransferase
PubMed: 29548922
DOI: 10.1016/j.cca.2018.03.003 -
Frontiers in Immunology 2019Sepsis is a complex of life-threating organ dysfunction in critically ill patients, with a primary infectious cause or through secondary infection of damaged tissues.... (Review)
Review
Sepsis is a complex of life-threating organ dysfunction in critically ill patients, with a primary infectious cause or through secondary infection of damaged tissues. The systemic consequences of sepsis have been intensively examined and evidences of local alterations and repercussions in the intestinal mucosal compartment is gradually defining gut-associated changes during sepsis. In the present review, we focus on sepsis-induced dysfunction of the intestinal barrier, consisting of an increased permeability of the epithelial lining, which may facilitate bacterial translocation. We discuss disturbances in intestinal vascular tonus and perfusion and coagulopathies with respect to their proposed underlying molecular mechanisms. The consequences of enzymatic responses by pancreatic proteases, intestinal alkaline phosphatases, and several matrix metalloproteases are also described. We conclude our insight with a discussion on novel therapeutic interventions derived from crucial aspects of the gut mucosal dynamics during sepsis.
Topics: Alkaline Phosphatase; Animals; Bacteria; Bacterial Translocation; Humans; Intestinal Mucosa; Peptide Hydrolases; Sepsis
PubMed: 31114571
DOI: 10.3389/fimmu.2019.00891 -
Orphanet Journal of Rare Diseases Jul 2018Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from dysfunction of the tissue non-specific alkaline phosphatase enzyme. Its manifestations are... (Review)
Review
BACKGROUND
Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from dysfunction of the tissue non-specific alkaline phosphatase enzyme. Its manifestations are extremely variable, ranging from early lethality to disease limited to the dentition. The disease is life-threatening when manifesting within the first six months of life, excepting the extremely rare benign perinatal hypophosphatasia. Childhood hypophosphatasia, defined as onset of symptoms between six months and eighteen years, can manifest as rickets, pain, decreased mobility, deficits of growth, and fractures. Historical treatment has generally involved a combination of dietary and rehabilitative interventions.
MAIN DOCUMENT
Asfotase alfa (Strensiq™), is a first-in-class bone-targeted recombinant tissue nonspecific alkaline phosphatase which has shown significant improvements in morbidity and mortality in patients with perinatal and infantile hypophosphatasia. Subsequent research has also shown improvements in morbidity for patients with childhood hypophosphatasia as measured by improvement in rickets, growth, strength, mobility, and quality of life. This enzyme replacement therapy has generally been well-tolerated, with most adverse reactions being mild-to-moderate in nature. The author shares their approach to decisions on commencement of ERT based from experience of managing approximately fifteen patients across the age spectrum. This approach focuses on assessing the severity of five key manifestations of childhood HPP: decreased mobility, pain, rickets, deficits of growth, and fractures.
Topics: Alkaline Phosphatase; Bone Diseases; Enzyme Replacement Therapy; Female; Humans; Hypophosphatasia; Immunoglobulin G; Male; Recombinant Fusion Proteins
PubMed: 30012160
DOI: 10.1186/s13023-018-0866-7