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

1)白细胞介素-11（IL-11）在骨髓脂肪形成和成骨细胞形成中的作用。我们之前的研究表明，在老年骨质疏松模型SAM-P6小鼠中，IL-11表达的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，我们研究了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可以抑制脂肪细胞分化所必需的PPARγ的转录活性，并刺激成骨细胞分化所必需的Smad1的转录活性。2)体内IL-11对骨代谢的影响接下来，我们用过表达人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小鼠更厚、更强。更重要的是，在衰老的IL-11转基因小鼠中没有观察到皮质骨丢失。这些结果表明，IL-11刺激骨形成，防止骨质流失。3) PPARγ参与骨髓成骨和脂肪生成我们利用稳定表达显性阴性PPARγ (DN-ST2)的小鼠骨髓基质细胞系ST2，研究了PPARγ是否参与骨髓基质细胞成骨和脂肪生成。DN-ST2细胞未分化为脂肪细胞。这些细胞在体外也没有分化成成骨细胞，这表明PPARγ的作用是成骨细胞形成所必需的。

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.