2004 Fiscal Year Final Research Report Summary
Differentiation-inducing signals in osteoblasts and its application for development of bone anabolic therapy
| Project/Area Number |
14370329
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
MATSUMOTO Toshio The University of Tokushima, Department of Medicine and Bioregulatory Sciences, Professor, 大学院・ヘルスバイオサイエンス研究部, 教授 (20157374)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Daisuke The University of Tokushima, Department of Medicine and Bioregulatory Sciences, lecturer, 大学院・ヘルスバイオサイエンス研究部, 講師 (60314853)
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| Project Period (FY) |
2002 – 2004
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| Keywords | bone formation / osteoblast / osteoporosis / IL-11 / transcription factor / AP-1 |
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| Research Abstract |
(1)Analysis of the AP-1/IL-11 signaling pathway
1.Transcriptional induction of fosB/deltafosB gene
Fluid shear stress (FSS) in vitro induced osteoblast expression of deltafosB, an AP-1 family transcription factor that is able to stimulate bone formation in vivo when over-expressed in transgenic mice. Further mechanistic studies revealed that FSS promoted fosB/deltafosB gene transcription in a manner dependent on calcium, ERK, and CREB, which acted via CRE-like sequences present in the mouse fosB gene upstream regulatory region.
2.Crosstalk between AP-1 and Smads
Small is a transcription factor that act downstream of BMP-2, a well-known inducer of bone formation. We found that FSS-activated AP-1 physically interacted and functionally cooperated with Smad1 to induce interleukin (IL)-11 gene transcription.
(2)Pathogenic roles of IL-11 in glucocorticoid-induced osteoporosis (GIO)
1.Anti-apoptotic effects of IL-11
PTH as well as IL-11 suppressed dexamethasone- and etoposide-induced osteoblast apoptosis by 50 %. Expression of Bcl-2, an anti-apoptotic factor, was down-regulated by these apoptosis inducers, which was restored by PTH or IL-11. And the effect of PTH was partially blocked by an anti-IL-11 neutralizing antibody
2.Transcriptional repression of IL-11 gene by dexamethasone
PTH induced IL-11 gene transcription, and this induction was blocked by dexamethasone. We found that these effects were both largely dependent on the AP-1 binding site in the IL-11 promoter.
Collectively, these results suggest that IL-11 plays a role in both pro-apoptotic effects of dexamethasone and anti-apoptotic effects of PTH in osteoblasts.
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