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Analysis of the effect of high glucose concentration and participation of insulin pathways on mesenchymal stem cells differentiation into osteoblastic lineages from bone marrow of spontaneously hypertensive rats


Diabetes mellitus type 1 and 2 can lead to skeletal abnormalities characterized by increased risk of bone fractures, delay fracture healing, osteoporosis, pain and lost productivity for patients. Optimal therapeutic methods for diabetic bone complication are still lacking, because it is not clear the mechanism through which diabetes mellitus leads to bone disorders. The hyperglycemia can be highlighted as a risk factor for bone disorder in diabetic patients not controlled. Spontaneously hypertensive rats (SHR) are considered a genetic model of essential arterial hypertension and peripheral insulin resistance that show damage in the bone architecture, however is unknown if the hypertensive genotype could affect the function and metabolism of mesenchymal stem cells (MSC) during the osteogenic differentiation. Due the changes in the insulin signaling pathway in adipocytes and aorta smooth muscle cell from SHR rats, in the first step of this work we will investigate in vitro if osteoblast also showed the same pattern of changes in the insulin signaling pathway. These data can reveal a new mechanism by which SHR rats, are more susceptible to damage in metabolism and architecture bone. In the second step will investigate if the hypertensive genotype could increase susceptibility in vitro of MSCs from marrow bone of SHR rats against the impact of high glucose concentration during osteogenic differentiation induced by ascorbic acid/beta-glycerophosphate/dexamethasone. Emphasize that the MSCs will be derived from young rats SHR (4 weeks) that not yet established the hypertension, to show only the influence of hypertensive genotype. The questions above will be evaluated and answered from the following parameters: genic expression of proteins from insulin signaling pathway, adipogenic and osteogenic transcription factors and collagen and non-collage proteins of bone matrix; cell proliferation; alkaline phosphatase activity; biological mineralization of extracellular matrix; expression and secretion of pro-inflammatory and osteoclastogenic cytokines; differential modulation of insulin signaling, inflammatory and mitogen activated protein kinase (MAPK) pathways. (AU)

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(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)
BALERA BRITO, VICTOR GUSTAVO; CHAVES-NETO, ANTONIO HERNANDES; DE BARROSA, THAMINE LANDIM; PENHA OLIVEIRA, SANDRA HELENA. Soluble yerba mate (Ilex Paraguariensis) extract enhances in vitro osteoblastic differentiation of bone marrow-derived mesenchymal stromal cells. Journal of Ethnopharmacology, v. 244, . (11/06070-5, 11/19458-1, 12/20547-1)
CHAVES NETO, ANTONIO H.; BRITO, VICTOR G. B.; LANDIM DE BARROS, THAMINE; DO AMARAL, CARIL C. F.; SUMIDA, DORIS H.; OLIVEIRA, SANDRA H. P.. Chronic high glucose and insulin stimulate bone-marrow stromal cells adipogenic differentiation in young spontaneously hypertensive rats. Journal of Cellular Physiology, v. 233, n. 9, p. 6853-6865, . (11/06070-5, 11/19458-1, 11/02558-3)
DE BARROS, THAMINE LANDIM; BALERA BRITO, VICTOR GUSTAVO; FERREIRA DO AMARAL, CARIL CONSTANTE; CHAVES-NETO, ANTONIO HERNANDES; CAMPANELLI, ANA PAULA; PENHA OLIVEIRA, SANDRA HELENA. Osteogenic markers are reduced in bone-marrow mesenchymal cells and femoral bone of young spontaneously hypertensive rats. Life Sciences, v. 146, p. 174-183, . (12/01924-9, 11/06070-5, 11/19458-1)

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