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Microvesicle/proteins-mediated paracrine signaling among bone and endothelial cells during bone development and regeneration

Grant number: 16/08888-9
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2016
Effective date (End): November 30, 2019
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal researcher:Willian Fernando Zambuzzi
Grantee:Célio Junior da Costa Fernandes
Home Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Associated research grant:14/22689-3 - Microvesicle/proteins-mediated paracrine signaling among bone and endothelial cells during bone development and regeneration, AP.JP
Associated scholarship(s):18/10856-3 - Complete characterization on exosome loading from endothelial cells under shear stress: a special attention to kinases and mRNA, BE.EP.DD


The mammals skeletal system contains a collection of cells, in a hierarchical manner, maintain bone formation throughout life. In this context, we know that osteogenesis is essential for bone deposition, as well as fracture healing through regenerative mechanisms; in addition, we know these processes often decrease with the progress of age, leading to bone loss and an increased incidence of fractures. Currently, bone defects constitute a public health problem since the life expectancy of the population has increased significantly over the last years. "Rebuild" the lost tissue is one of the great challenges of surgeons in the area, often requiring the application of a biomaterial that allows functional repair of the lost tissue. Despite its medical, social and economic importance, little progress has been made regarding the bioassay methodologies able to rank new therapies. We now know that the bone development is a complex event and orchestrated by intercellular signaling as it has been shown by Prof. RH Adams, from Max Planck Institute for Molecular Biomedicine, recently published in Nature. These works justify our interest in studying the crosstalk between the osteogenic and endothelial lineages, emphasizing the importance of knowing the repertoire of molecules secreted by osteoblasts and endothelial cells during bone remodeling. In this context, we will investigate: 1) the interplay between bone and endothelial cells - evaluating vesicles secreted and extracellular proteins in this context; 2) characterization of a functional blood vessel tissue equivalent and its impact on osteoblasts and osteoclasts; 3) check through the biomarkers listed in previous step, its conservation during the intramembranous and endochondral embryonic development; 4) the angiogenic-coupled osteogenesis during tissue regeneration of the alveolar bone; In this project, we celebrate the participation of international researchers such as: Prof. Anna Teti (Italy, expert in bone cell energy metabolism and molecular characteristics which determine the phenotype of osteoblasts, osteoclasts and osteocytes), Professor Hans van Leeuwen (Netherlands, expert in microvesicles extracellular analysis) and Prof. Suvro Chartjee (India, expert in endothelial cells, Shear stress and NO signaling). This assembly of international researchers is the result of INTERBONE, Consorcium that Prof. William Zambuzzi (proponent of this project) integrates as principal investigator since 2011. Thus, among the expected outcomes for this project include: 1) implementation in the IBB - UNESP, research on mineralized tissues, with multi-user equipment capable of attend this community; 2) multidisciplinary; 3) maintenance of national and international partnerships, contributing to exchanges and training of our undergraduate and graduate students; 4) contribution with results that can be explored in the context of applied research. (AU)

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Scientific publications (6)
(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)
FERNANDES, CELIO JR DA COSTA; ZAMBUZZI, WILLIAN FERNANDO. Fibroblast-secreted trophic factors contribute with ECM remodeling stimulus and upmodulate osteocyte gene markers in osteoblasts. Biochimie, v. 168, p. 92-99, JAN 2020. Web of Science Citations: 0.
JANMAAT, VINCENT T.; LIU, HUI; DA SILVA, RODRIGO A.; WISSE, PIETER H. A.; SPAANDER, MANON C. W.; TEN HAGEN, TIMO L. M.; SMITS, RON; BRUNO, MARCO J.; FUHLER, GWENNY M.; PEPPELENBOSCH, MAIKEL P. HOXA9 mediates and marks premalignant compartment size expansion in colonic adenomas. Carcinogenesis, v. 40, n. 12, p. 1514-1524, DEC 2019. Web of Science Citations: 1.
DA COSTA FERNANDES, CELIO JR.; VEIGA, MARIANA R.; SERRAO PERACOLI, MARIA TEREZINHA; ZAMBUZZI, WILLIAN F. Modulatory effects of silibinin in cell behavior during osteogenic phenotype. Journal of Cellular Biochemistry, v. 120, n. 8, p. 13413-13425, AUG 2019. Web of Science Citations: 1.
FERNANDES, CELIO JR DA COSTA; PINTO, THAIS SILVA; KANG, HA RAM; PADILHA, PEDRO DE MAGALHAES; KOH, IVAN HONG JUN; LEOPOLDO CONSTANTINO, VERA REGINA; ZAMBUZZI, WILLIAN F. Layered Double Hydroxides Are Promising Nanomaterials for Tissue Bioengineering Application. ADVANCED BIOSYSTEMS, v. 3, n. 7 JUL 2019. Web of Science Citations: 1.
DA SILVA, RODRIGO A.; FERNANDES, CELIO JR DA C.; FELTRAN, GEORGIA DA S.; GOMES, ANDERSON M.; DE CAMARGO ANDRADE, AMANDA FANTINI; ANDIA, DENISE C.; PEPPELENBOSCH, MAIKEL P.; ZAMBUZZI, WILLIAN F. Laminar shear stress-provoked cytoskeletal changes are mediated by epigenetic reprogramming of TIMP1 in human primary smooth muscle cells. Journal of Cellular Physiology, v. 234, n. 5, p. 6382-6396, MAY 2019. Web of Science Citations: 5.
DA COSTA FERNANDES, CELIO J.; FERREIRA, MARCEL RODRIGUES; BEZERRA, FABIO J. B.; ZAMBUZZI, WILLIAN F. Zirconia stimulates ECM-remodeling as a prerequisite to pre-osteoblast adhesion/proliferation by possible interference with cellular anchorage. JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE, v. 29, n. 4 APR 2018. Web of Science Citations: 4.

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