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Extracellular matrix vesicles (MVs) mimetic systems to study the regulation of the biomineralization process: proteoliposomes containing NPP1 and Annexin V

Abstract

Bone tissue is composed by a combination of a collagen matrix and a mineral matrix, which is formed by calcium phosphate crystals, generating the hydroxyapatite structure. This process of mineral accumulation in the bone tissue is called biomineralization and is carried out by cells called osteoblasts, through the release of matrix vesicles (MVs). These vesicles arise by budding from the cell surfaces and are secreted in specific sites of the beginning of biomineralization in the bone matrix. MVs contain high concentrations of Ca2+ ions and inorganic phosphate (Pi), providing a suitable microenvironment for the initial formation and propagation of hydroxyapatite crystals. In order to this process occurs correctly, several proteins/enzymes are needed as well as microenvironments with very specific conditions. Special attention should be given to certain proteins present in MVs: Annexin V (AnxA5), alkaline phosphatase (TNAP) and nucleoside triphosphate diphosphohydrolase 1 (NPP1). These proteins regulate the formation of calcium phosphate crystals, thus directly acting on bone mineralization. Among the annexins, specifically Annexin V, a protein of ~ 35 kDa, is responsible for the formation of calcium channels through its association with both the internal and external surface of the MVs membrane. Annexins are also responsible for disruption of the cell membrane, which in turn results in apoptosis. TNAP is a nonspecific phosphomonohydrolase capable of hydrolyzing phosphate monoesters, pyrophosphate, phosphate diesters, as well as catalyze transphosphorylation reactions. It is inserted into the plasma membrane of MVs through a glycosylphosphatidylinositol (GPI) anchor and is called "alkaline" for its ability to carry out these substrates hydrolysis reactions more efficiently at pHs above neutral (pH 8-11). Furthermore, TNAP plays a crucial role in limiting the concentration of extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to maintain a Pi/PPi ratio suitable for normal bone mineralization. The primary function of TNAP is to degrade ePPi, which is produced ectoplasmically by NPP1. Thus, NPP1 has the function of inhibiting precipitation of hydroxyapatite due to its property of PPi generation, thus controlling the Pi/PPi ratio. In this project, we intend to study specifically the involvement of the protein AnxA5 and the enzyme NPP1, both reconstituted into liposomes, with the objective of forming MVs mimetic systems and study how these combinations may regulate and/or modulate the mineralization process mediated by these vesicles. It should be noted that it is always given a secondary role to NPP1 (TNAP has the main role), thus we aim to unveil the true function of this enzyme in the biomineralization process.ncher com o resumo do projeto de pesquisa, em inglês. Máximo 4000 caracteres. Este resumo será usado para a análise preliminar da proposta e para divulgação pública.> (AU)

Scientific publications (10)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DERRADI, R.; BOLEAN, M.; SIMAO, A. M. S.; CASELI, L.; MILLAN, J. L.; BOTTINI, M.; CIANCAGLINI, P.; RAMOS, A. P. Cholesterol Regulates the Incorporation and Catalytic Activity of Tissue-Nonspecific Alkaline Phosphatase in DPPC Monolayers. Langmuir, v. 35, n. 47, p. 15232-15241, NOV 26 2019. Web of Science Citations: 0.
CRUZ, M. A. E.; SOARES, M. P. R.; PAZIN, W.; ITO, A. S.; FUKADA, S. Y.; CIANCAGLINI, P.; RAMOS, A. P. Interface-driven Sr-morin complexation at Langmuir monolayers for bioactive coating design. COLLOIDS AND SURFACES B-BIOINTERFACES, v. 181, p. 856-863, SEP 1 2019. Web of Science Citations: 0.
SPER SIMAO, ANA MARIA; BOLEAN, MAYTE; FAVARIN, BRUNO ZOCCARATTO; VESCHI, EKEVELINY AMABILE; TOVANI, CAMILA BUSSOLA; RAMOS, ANA PAULA; BOTTINI, MASSIMO; BUCHET, RENE; MILLAN, JOSE LUIS; CIANCAGLINI, PIETRO. Lipid microenvironment affects the ability of proteoliposomes harboring TNAP to induce mineralization without nucleators. JOURNAL OF BONE AND MINERAL METABOLISM, v. 37, n. 4, p. 607-613, JUL 2019. Web of Science Citations: 3.
CRUZ, M. A. E.; ZANATTA, M. B. T.; DA VEIGA, M. A. M. S.; CIANCAGLINI, P.; RAMOS, A. P. Lipid-mediated growth of SrCO3/CaCO3 hybrid films as bioactive coatings for Ti surfaces. Materials Science & Engineering C-Materials for Biological Applications, v. 99, p. 762-769, JUN 2019. Web of Science Citations: 1.
PLAUT, JUSTIN S.; STRZELECKA-KILISZEK, AGNIESZKA; BOZYCKI, LUKASZ; PIKULA, SLAWOMIR; BUCHET, RENE; MEBAREK, SAIDA; CHADLI, MERIEM; BOLEAN, MAYTE; SIMAO, ANA M. S.; CIANCAGLINI, PIETRO; MAGRINI, ANDREA; ROSATO, NICOLA; MAGNE, DAVID; GIRARD-EGROT, AGNES; FARQUHARSON, COLIN; ESENER, SADIK C.; MILIAN, JOSE L.; BOTTINI, MASSIMO. Quantitative atomic force microscopy provides new insight into matrix vesicle mineralization. Archives of Biochemistry and Biophysics, v. 667, p. 14-21, MAY 30 2019. Web of Science Citations: 1.
ANDRADE, MARCO A. R.; DERRADI, RAFAEL; SIMAO, ANA M. S.; MILLAN, JOSE LUIS; RAMOS, ANA P.; CIANCAGLINI, PIETRO; BOLEAN, MAYTE. Is alkaline phosphatase biomimeticaly immobilized on titanium able to propagate the biomineralization process?. Archives of Biochemistry and Biophysics, v. 663, p. 192-198, MAR 15 2019. Web of Science Citations: 2.
CRUZ, MARCOS A. E.; TOVANI, CAMILA B.; FAVARIN, BRUNO Z.; SOARES, MARIANA P. R.; FUKADA, SANDRA Y.; CIANCAGLINI, PIETRO; RAMOS, ANA P. Synthesis of Sr-morin complex and its in vitro response: decrease in osteoclast differentiation while sustaining osteoblast mineralization ability. JOURNAL OF MATERIALS CHEMISTRY B, v. 7, n. 5, p. 823-829, FEB 7 2019. Web of Science Citations: 2.
TOVANI, C. B.; FARIA, A. N.; CIANCAGLINI, P.; RAMOS, A. P. Collagen-supported CaCO3 cylindrical particles enhance Ti bioactivity. SURFACE & COATINGS TECHNOLOGY, v. 358, p. 858-864, JAN 25 2019. Web of Science Citations: 1.
BOTTINI, MASSIMO; MEBAREK, SAIDA; ANDERSON, KAREN L.; STRZELECKA-KILISZEK, AGNIESZKA; BOZYCKI, LUKASZ; SPER SIMAO, ANA MARIA; BOLEAN, MAYTE; CIANCAGLINI, PIETRO; PIKULA, JOANNA BANDOROWICZ; PIKULA, SLAWOMIR; MAGNE, DAVID; VOLKMANN, NIELS; HANEIN, DORIT; MILLAN, JOSE LUIS; BUCHET, RENE. Matrix vesicles from chondrocytes and osteoblasts: Their biogenesis, properties, functions and biomimetic models. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1862, n. 3, p. 532-546, MAR 2018. Web of Science Citations: 25.
FAVARIN, B. Z.; ANDRADE, M. A. R.; BOLEAN, M.; SIMAO, A. M. S.; RAMOS, A. P.; HOYLAERTS, M. F.; MILLAN, J. L.; CIANCAGLINI, P. Effect of the presence of cholesterol in the interfacial microenvironment on the modulation of the alkaline phosphatase activity during in vitro mineralization. COLLOIDS AND SURFACES B-BIOINTERFACES, v. 155, p. 466-476, JUL 1 2017. Web of Science Citations: 9.

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