Wnt and Hedgehog signaling in vetebrate limb and skeleta

在脊椎动物胚胎发育的早期，细胞-细胞信号转导起着重要作用。我们感兴趣的是Wnt和Hedgehog信号通路在脊椎动物胚胎发育，特别是肢体发育和骨骼形态发生控制中的作用机制。在肢体发育的早期，包括Wnt和Hedgehog家族成员在内的信号分子决定了晚期结构(即骨骼元素)形成的地点和时间。肢体的骨骼形态形成是通过软骨内成骨发生的，其中软骨细胞(它们形成软骨)和成骨细胞(它们分泌骨基质)首先从间充质凝聚中分化出来。紧随其后的是软骨细胞和成骨细胞的连续增殖和成熟，它们受到严格的调控和协调，以确保骨骼系统的适当形态发生。通过对Wnt信号成分失活或异位表达的突变小鼠的分析，我们发现Wnt5a与许多其他WNTs不同，它通过一种新的途径来拮抗经典的Wnt途径来调节胚胎发育和可能抑制肿瘤的形成。此外，我们还发现在发育中的滑膜关节中，几个Wnt基因以重叠和互补的模式表达，其中β-catenin蛋白水平和转录活性上调。我们证明Wnt/β-catenin信号通路是诱导滑膜关节早期形成的必要条件和充分条件。此外，我们还发现Wnt/β-catenin信号通路也控制着成骨细胞和软骨细胞向间充质祖细胞的分化。WNT/β-catenin信号通路在软骨细胞肥大的调节中也是必不可少的。我们的结果表明，通过增强Wnt/β-catenin信号的强度，现在可以仅沿软骨细胞或成骨细胞谱系引导祖细胞和干细胞的分化。我们的研究工作表明，Wnt/β-catenin信号通路是骨质疏松症和骨性关节炎治疗发展的关键靶点。

Early in vertebrate embryonic development, cell-cell signaling plays important roles. We are interested in the mechanistic understanding of Wnt and hedgehog signaling pathways in the control of vertebrate embryonic development, in particular, limb development and skeletal morphogeneis. Early in limb development, signaling molecules which include the Wnt and hedgehog family members determines where and when the late structures, ie, skeletal elements will form. Skeletal morphogeneis in the limb occurs through endochondral bone formation in which chondrocytes (they form the cartilage) and osteoblasts (they secrete bone matrix) are first differentiated from mesenchymal condensations. This is followed by sequential proliferation and maturation of both chondrocytes and osteoblasts, which are tightly regulated and coordinated to ensure proper morphogenesis of the skeletal system. Through analyzing mutant mice in which Wnt signaling components are either inactivated or ectopically expressed, we have found that Wnt5a, in contrast to many other Wnts, signal through a novel pathway to antagonize the canonic Wnt pathway in regulating embryonic development and possibly in suppressing tumor formation.In addition, we have found that several Wnt genes are expressed in overlapping and complementary patterns in the developing synovial joints, where beta-catenin protein levels and transcription activity were up-regulated. We demonstrated that that Wnt/ beta-catenin signaling pathway is both necessary and sufficient to induce early steps of synovial joint formation. Furthermore, we found that the Wnt/ beta-catenin signaling pathway also controls the differentiation of osteoblasts and chondrocytes from mesenchymal progenitor cells. Wnt/ beta-catenin signaling pathway is also essential in the regulation of chondrocyte hypertrophy. Our results indicate that by manupilating the strength of the Wnt/ beta-catenin signaling, it is now possible to direct the differentiation of progenitor cells and stem cells along only the chondrocyte or osteoblast lineage. Our research work demonstrated that the Wnt/ beta-catenin signaling pathway is a critical target for the therapeutic development of both osteoporosis and osteoarthritis.