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조골세포 사멸 및 분화에서 GSK3b의 역할

Authors
윤, 선일
Degree
Doctor (2010)
Abstract
" Dfferentiation of osteoblasts is critically involved in bone formation and requires several signal pathways. One of the important pathways is the Wnt signaling where GSK3 plays a key role in regulation of β-catenin activity, a major effector, through phosphorylation. Glucocorticoids (GCs) are known to induce osteoporosis via a decrease of differentiation and apoptosis of osteoblasts and osteocytes in part. However, the detailed mechanism of GC-induced osteoporosis has not been clearly determined.

This study showed that dexamethasone (Dex) induced apoptosis of MC3T3-E1 osteoblasts through the GC receptor. Dex activated GSK3β, and inhibition of GSK3β by lithium, a pharmacological antagonist, or gene knock-down by siRNA prevented the Dex-induced apoptosis. Unexpectedly, Dex also activated p38 mitogen-activated protein kinase (p38 MAPK); however, the inhibition of p38 MAPK further increased apoptosis in Dex-treated osteoblasts. These results suggest that p38 MAPK might protect against Dex-induced apoptosis of osteoblasts.

Etoposide, a genotoxic agent, increased apoptosis of C3H10T1/2 osteoblast progenitor cells by the activation of both caspase-3 and GSK3β. The pharmacological inhibition (lithium) or gene knock-down (siRNA) of GSK3β protected the cells from apoptosis. This is quite similar to the results of Dex-induced apoptosis. In addition, etoposide decreased expression of Bcl-2, an anti-apoptotic protein, in the C3H10T1/2 cells. LiCl completely recovered the Bcl-2 expression as shown by both the mRNA and the protein expression levels.

It has recently been reported that Dex decreases differentiation and mineralization of osteoblasts, but its mechanism is not certainly understood. The present study also showed that Dex were associated with osteoblast differentiation by employing MC3T3-E1 cells, an osteoblast cell line. Dex decreased osteocalcin mRNA level compared to that of un-treated cells at an early differentiation period. Interestingly, Dex continuously accumulated the expression of heat shock protein 25 (HSP25). Gene knock-down of HSP25 by siRNA recovered osteocalcin expression up to control level. Furthermore, treatment with lithium decreased HSP25 expression and also recovered osteocalcin expression. These results suggest that HSP25 induction was associated with osteoblast differentiation via osteocalcin modulation and mediated by GSK3β.

In summary, Dex-induced GSK3β activation triggered apoptosis of osteoblasts and was associated with osteoblast differentiation. Therefore, GSK3β appears to play a key role in the fate and function of osteoblasts. The results of this study provide additional insights into the pathogenic mechanism of GC-induced osteoporosis.

"
Keywords
OsteobalstsApoptosisDexamethasoneGSK3bp38 MAPKEtoposideDifferentiationHSP25Osteocalcin
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Theses > School of Medicine / Graduate School of Medicine > Doctor
AJOU Authors
윤, 선일
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