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Remodeling of the extracellular matrix of the bone marrow in malnutrition: the possible relationship Akt pathway and expression of fibronectin and metalloproteinase

Grant number: 12/19913-3
Support type:Regular Research Grants
Duration: December 01, 2012 - November 30, 2014
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Primavera Borelli Garcia
Grantee:Primavera Borelli Garcia
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:José Guilherme Xavier ; Marcelo Macedo Rogero ; Orlando Garcia Ribeiro Filho ; Ricardo Ambrósio Fock ; Silvya Stuchi Maria-Engler

Abstract

Malnutrition remains a major global public health problems affecting developing countries, but especially developing countries. Children, the elderly and hospitalized individuals under parenteral feeding or who have eating disorders are the most vulnerable to malnutrition. Malnutrition can cause several physiological changes and these depend on the cause of malnutrition, age and sex of the individual. Some studies have shown that malnutrition can cause changes in the extracellular matrix (ECM) that makes up the bone marrow stroma. Our group demonstrated that malnourished animals have bone marrow hypoplasia, reduced stem cell / progenitor and changes in mec with increased laminin, fibronectin and thrombospondin. We also demonstrated the presence of different isoforms of fibronectin (unpublished data). The alterations found in the ECM may be due to remodeling process comprising the synthesis and degradation of ECM. The MEC tissue is degraded and synthesized through a process called remodeling, this physiological process that occurs during development, maintenance of normal tissue, tissue repair and some pathological processes such as atherosclerosis. Throughout tissue repair promotes the deposition of ECM tissue integrity and its functionality, with one inappropriate or excessive deposition leads to an impairment of organ function. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes associated with degradation and the "turnover" of the proteins comprising the ECM, thereby taking an important role in the remodeling thereof. Some studies in the literature have noted the presence of MMPs in the bone marrow stroma and that the balance between MMPs and their inhibitors is critical to the integrity of the ECM, thereby participating in the maintenance of hemopoese. AKT (serine-threonine kinase) participates in diverse cellular functions such as; growth, proliferation, migration, apoptosis, angiogenesis and glucose metabolism. The signaling pathway can be initiated by growth factors, cytokines by ECM proteins such as FN, involved with the synthesis of MMPs and fibronectin isoforms. The AKT signaling pathway may be involved in the alternative splicing of the FN. It is also known that the AKT signaling pathway is involved in the induction of expression of MMP-2 and MMP-9 and demonstrate evidence that NF induces the expression of MMP-9 activation through AP-1 and VLA -5, main integrin interaction with FN and coma present in stem cells / progenitor hemopoéticas also be involved in the expression of MMP-9. Thus, the AKT signaling pathway is a common element between the FN and MMP, and the presence of FN isoforms. Preliminary results of our group (unpublished data) demonstrate quantitative changes in total AKT and phosphorylated AKT OF total cells in the bone marrow of malnourished animals compared to the controls. Thus the aim of this study is to evaluate the remodeling of the ECM in the bone marrow, evaluating and characterizing the AKT pathway in the expression of MMP-2 and MMP-9 and FN in a murine model of protein malnutrition. (AU)