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Prevention and treatment of bone diseases caused by glucocorticoid medicines

A technology for glucocorticoids and bone diseases, applied in the field of biotechnology, can solve problems such as unclear specific mechanisms

Active Publication Date: 2014-10-15
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Runx2 and Osteorix (Osx) are key transcription factors that initiate osteoblast differentiation, while adipocyte differentiation is regulated and affected by other factors, but many of the specific mechanisms are still unclear

Method used

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  • Prevention and treatment of bone diseases caused by glucocorticoid medicines
  • Prevention and treatment of bone diseases caused by glucocorticoid medicines
  • Prevention and treatment of bone diseases caused by glucocorticoid medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Establishment of Dex-induced osteoporosis model

[0091] In order to explore the mechanism of Dex-induced osteoporosis, in this example, the inventors first established a Dex-induced osteoporosis model in mice. After 6-8 weeks of mice were subcutaneously administered Dex for 5 weeks, the femurs were used for microCT analysis.

[0092] The results showed that the mice treated with Dex had decreased bone mineral density and bone mass, decreased bone trabeculae, and showed obvious bone loss phenotype ( figure 1 A, figure 1 B). Histological examination found that compared with the control mice, the Dex-administered mice not only decreased the density of trabecular bone, but also had a large amount of fat in the bone marrow ( figure 1 C), consistent with the clinical phenotype.

Embodiment 2

[0094] Dex inhibits osteoblast differentiation and enhances the potential of BMSCs to differentiate into adipocytes

[0095] In order to detect whether the differentiation ability of BMSCs in Dex-treated mice is changed, the inventors isolated primary BMSCs from Dex mice and control mice, and cultured them in vitro to detect the osteogenic differentiation ability induced by BMP2. The two groups of BMSCs were induced by BMP2, and the expression of osteoblast-related genes was detected at different time points (3 days, 7 days, 14 days, 21 days) to judge the ability of osteogenic differentiation.

[0096] The results showed that in the BMSCs of Dex mice at different time points induced by BMP2, the marker genes Osteorix (Osx), type I collagen (Collagen type I, Col1a1) and osteocalcin (Osteocalcin, Ocn) were all underexpressed, while In normal BMSCs, the expression of these genes increased with the induction of BMP2 ( figure 2 A). In contrast, aP2 and Glut4, which are related t...

Embodiment 3

[0100] Under Dex treatment, C / EBPalpha factor was highly expressed

[0101] It was previously found that the key transcription factor C / EBPalpha in adipocyte differentiation is down-regulated in osteoblast differentiation, and its overexpression can disrupt the balance of osteogenic / adipogenic differentiation. In the osteoporosis model, it was found that the osteogenic / adipogenic differentiation balance of BMSCs has been disrupted by Dex. This example is used to detect the change of the expression level of C / EBPalpha.

[0102] First of all, the inventors detected the level of C / EBPalpha in the primary BMSCs and C3H10T1 / 2 cells, and found that the mRNA and protein levels of C / EBPalpha factors were significantly lower in the BMSCs of Dex mice ( image 3 A) and Dex-treated C3H10T1 / 2 ( image 3 B) are significantly higher than the control, and maintain this high level in 21 days of osteogenic differentiation. Immunohistochemical experiments found that the protein level of C / EBPa...

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Abstract

The invention relates to prevention and treatment of bone diseases caused by glucocorticoid medicines. Concretely, the invention relates to application of Wnt signal pathway to prevention and treatment of bone diseases caused by glucocorticoid medicines. Expression of C / EBPalpha factor is down regulated at a later period that BMP2 induces a mouse mesenchymal stem cell line C3H10T1 / 2 to be differentiated into osteoblast, and overexpression of the factor can inhibit differentiation of osteoblast. The reason causing down-regulated expression of C / EBPalpha is that distal promoters (-1286bp / -1056bp) of C / EBPalpha are subjected to hypermethylation at the differentiation later-period of osteoblast and are silenced. Interruption of the methylation process promotes high expression of C / EBPalpha and leads to osteogenic / adipogenic differentiation unbalance. A Dex-induced osteoporosis model proves that Wnt / beta-catenin signal pathway has important regulation and control effects on expression and methylation of C / EBPalpha in differentiation of osteoblast. A stimulant / activator of the pathway is capable of rescuing osteogenic / adipogenic differentiation unbalance caused by Dex.

Description

technical field [0001] The invention belongs to the fields of biotechnology, tissue stem cell differentiation control and immune regulation, and specifically relates to the application of a Wnt signaling pathway agonist and CEBPalpha inhibitor in the prevention / treatment of bone disease caused by glucocorticoid drugs. Background technique [0002] Dexamethasone (Dex) is a synthetic glucocorticoid drug widely used clinically as an immune response inhibitor. However, long-term use can lead to osteoporosis symptoms such as bone loss and decreased bone density, and there is currently no effective treatment. [0003] It has been found clinically that long-term use of dexamethasone (Dex) will not only lead to severe osteoporosis, but also be accompanied by bone marrow fat. Osteoblasts and adipocytes are derived from the same pluripotent adult stem cells: bone marrow mesenchymal stem cells (BMSCs), and there is a competitive balance in the differentiation of the two, so a large am...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P19/00A61P19/10A61P19/08
Inventor 张晓玲李姣
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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