The Regulation of Bone-Remodeling by Signals mediated by Phosphorylation

(1)C/EBPβ在间充质干细胞向成骨细胞和脂肪细胞分化中的作用我们发现C/EBPβ不仅可以诱导间充质干细胞分化为脂肪细胞，还可以诱导其向成骨细胞分化。此外，C/EBPβ的一个亚型，LIP，以显性-负向方式阻止脂肪生成，但作为Cbfa1的辅助因子显示出成骨作用。JNK/c-jun信号在破骨细胞分化中的作用RANKL促进小鼠单核细胞系RAW264细胞向破骨细胞分化。RANKL还能激活JNK、c-jun和AP-1的转录。显性阴性的JNK或c-Jun过表达可通过阻断JNK或c-Jun信号的激活而显著抑制RANKL刺激RAW264细胞形成破骨细胞。提示JNK/c-jun信号在RANKL诱导破骨细胞分化中起重要作用。(3)肿瘤坏死因子-α对成骨细胞分化的抑制作用和诱导细胞凋亡的作用。突变型L-kBα过表达阻断核因子-kB信号，可显著抑制肿瘤坏死因子对未分化间充质细胞向成骨细胞分化的影响。相反，突变型L-kBα的过表达加速了肿瘤坏死因子诱导的细胞凋亡。结果提示，肿瘤坏死因子可抑制间充质细胞向成骨细胞分化，并通过调节核因子-kB信号途径促进细胞凋亡。

(1) Role of C/EBP beta in the differentiation of mesenchymal stem cells into osteoblasts and adipocytesWe found that C/EBP beta is able to induce the differentiation of mesenchymal stem cells into not only adipocytes but also osteoblasts. In addition, an isoform of C/EBP beta, LIP, blocks the adipogenesis in a dominant-negative fashion, but exhibits osteogenic action as a co-factor for Cbfa1. Our data provide the new insight into the understanding the molecular mechanisms that determine the direction of mesenchymal stem cells in bone.(2) The role of JNK/c-Jun signaling in osteoclast differentiationTreatment of RANK ligand (RANKL) promoted the osteoclastic differentiation of mouse monocytic cell line RAW264 cells. RANKL also activated JNK, c-Jun and transcription of AP-1. Overexpression of dominant negative JNK or c-Jun markedly inhibited the formation of osteoclasts by RANKL stimulation in RAW264 cells by blocking the activation of JNK or c-Jun signaling. The data suggest the crucial role of JNK/c-Jun signaling in the osteoclast differentiation by RANKL.(3) Suppressive effects on osteoblastic differentiation and Induction of its apoptosis by TNF-alphaWe observed that TNF suppressed the osteoblastic differentiation of mesenchymal stem cells and promoted the apoptosis of mature osteoblasts. Blockade of NF-kB signaling by overexpression of mutant l-kB alpha profoundly inhibited the effect of TNF on osteoblastic differentiation of undifferentiated mesenchymal cells. In contrast, overexpression of the mutant l-kB alpha accelerated the apoptosis induced by TNF. The data suggest that TNF suppresses osteoblastic differentiation of mesenchymal cells and accelerated the apoptosis by regulating NF-kB signaling.