Role of bone marrow adipogenesis for bone formation and its abnormality in senile osteoporosis

骨髓脂肪生成对骨形成的作用及其异常在老年骨质疏松中的作用

• 批准号: 13671150
• 负责人: TAKEUCHI Yasuhiro
• 金额: $ 2.56万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671150/
• 关键词: osteoblast; adipocyte; interleukin-11; PPARγ; bone marrwo stromal cell; transgenio mine; osteoporosis; bone formation; Smad

1) Role of interteukin-11(IL-11) in adipogenesis and osteoblastogenesis in bone marrow.We have previously shown that decreased IL-11 expression is tightly associated with impaired bone formation in senile osteoporosis model SAM-P6 mice. To further investigate how IL-11 is involved in bone metabolism, we examined effects of IL-11 on differentiation of both adipocytes and osteoblasts in bone marrow. Our results indicate that IL-11 inhibits transcriptional activity of PPARγ, essential for adipocyte differentiation, and stimulates that of Smad1, indispensable for osteoblastic differentiation2) In vivo effects of IL-11 on bone metabolismWe next investigated effects of IL-11 on bone metabolism in vivo using tansgenic mice overexpressing human IL-11 gene. Bone formation was stimulated but bone resorption was not changed in IL-11 transgenic mice, resulting in thicker and stronger cortical bone than control littermates. More importantly, cortical bone loss was not observed in IL-11 transgenic mice with aging. These results suggest that IL-11 stimulates bone formation and prevents bone loss with aging.3) Involvement of PPARγ in osteoblastogenesis and adipngenflsis in bone marrowWe examined if PPARγ was involved in osteoblastogenesis as well as adipogenesis in bone marrow stromal cells, using mouse bone marrow stromal cell line ST2 stably expressing dominant negative PPARγ (DN-ST2). DN-ST2 cells were confirmed not to be differentiated into adipocytes. These cells were also not differentiated into osteoblasts in vitro, suggesing that PPARγ actions are required for osteobliastogenesis.

1)白细胞介素-11（IL-11）在骨髓脂肪生成和成骨细胞生成中的作用我们先前已经表明，在老年骨质疏松模型SAM-P6小鼠中，IL-11表达降低与骨形成受损密切相关。为了进一步研究IL-11如何参与骨代谢，我们检测了IL-11对骨髓中脂肪细胞和成骨细胞分化的影响。我们的研究结果表明IL-11抑制了脂肪细胞分化所必需的PPARγ的转录活性，并刺激了成骨细胞分化所必需的Smad 1的转录活性。2）IL-11对骨代谢的体内影响我们接下来使用过表达人IL-11基因的转基因小鼠研究了IL-11对体内骨代谢的影响。IL-11转基因小鼠的骨形成受到刺激，但骨吸收没有改变，导致皮质骨比对照组更厚、更强。更重要的是，在IL-11转基因小鼠中未观察到皮质骨丢失。这些结果表明IL-11刺激骨形成并防止随年龄增长的骨丢失。3）过氧化物酶体增殖物激活受体γ（PPARγ）参与骨髓成骨细胞和成脂细胞的形成我们使用稳定表达显性负性过氧化物酶体增殖物激活受体γ（DN-ST 2）的小鼠骨髓基质细胞系ST 2检测了PPARγ是否参与骨髓基质细胞的成骨细胞和成脂细胞的形成。证实DN-ST 2细胞未分化为脂肪细胞。这些细胞在体外也不能分化成成骨细胞，这表明成骨细胞的形成需要PPARγ的作用。

项目成果

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