Wnt signaling and osteoblastogenesis
Wnt signaling and osteoblastogenesis
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DOI：
10.1007/s11154-006-9002-4
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发表时间：
2006-06-01
影响因子：
8.2
通讯作者：
Komm, Barry S.
中科院分区：
文献类型：
--
作者：
Bodine, Peter V. N.;Komm, Barry S.
Writs是一大类生长因子，介导基本的生物过程，如胚胎发生、器官发生和肿瘤发生。这些蛋白结合到由卷曲（FZD） g蛋白偶联受体（gpcr）和低密度脂蛋白受体相关蛋白（LRP）组成的膜受体复合物。这种配体-受体复合物的形成启动了许多细胞内信号级联反应，包括经典/ β -连环蛋白途径，以及几种gpcr介导的非经典途径。近年来，典型的Writ信号已被证明在骨形成的控制中发挥重要作用。临床研究发现LRP-5的突变与骨矿物质密度和骨折有关。例如，LRP-5的功能丧失突变导致骨质疏松性假性胶质瘤综合征，而功能获得突变导致高骨量表型。对Wnt-10b、lfp -5/6、分泌的卷曲相关蛋白-1、dickkopf-2、Axin-2和β -catenin等Writ通路组分的敲除和转基因小鼠模型的研究表明，典型信号调节成骨细胞生理的大多数方面，包括增殖、分化、骨基质形成/矿化和凋亡，以及与破骨细胞发生和骨吸收的耦合。在这个快速发展的研究领域，未来的研究应该集中在阐明Wnt/FZD在控制骨细胞功能中的特异性，非规范通路在骨骼重塑中的作用，以及Writs对破骨细胞谱系细胞的直接影响。
Writs are a large family of growth factors that mediate fundamental biological processes like embryogenesis, organogenesis and tumorigenesis. These proteins bind to a membrane receptor complex comprised of a frizzled (FZD) G-protein-coupled receptor (GPCRs) and a low-density lipoprotein (LDL) receptor-related protein (LRP). The formation of this ligand-receptor complex initiates a number of intracellular signaling cascades that includes the canonical/beta-catenin pathway, as well as several GPCR-mediated noncanonical pathways. In recent years, canonical Writ signaling has been shown to play a substantial role in the control of bone formation. Clinical investigations have found that mutations in LRP-5 are associated with bone mineral density and fractures. For example, loss-of-function mutations in LRP-5 cause osteoporosis pseudoglioma syndrome, while gain-of-function mutations lead to high bone mass phenotypes. Studies of knockout and transgenic mouse models for Writ pathway components like Wnt-10b, LRP-5/6, secreted frizzled-related protein-1, dickkopf-2, Axin-2 and beta-catenin have demonstrated that canonical signaling modulates most aspects of osteoblast physiology including proliferation, differentiation, bone matrix formation/mineralization and apoptosis as well as coupling to osteoclastogenesis and bone resorption. Future studies in this rapidly growing area of research should focus on elucidating Wnt/FZD specificity in the control of bone cell function, the role of noncanonical pathways in skeletal remodeling, and direct effects of Writs on cells of the osteoclast lineage.