经典Wnt信号通路对骨代谢的调节作用

Wnt信号通路是一个调控细胞生长、发育和分化的重要信号途径。越来越多的证据表明,经典Wnt信号通路在成骨细胞的分化进程及骨形成过程中扮演着重要角色。本文就经典Wnt信号通路中已知的与骨代谢相关的各个成分及其功能,以及对通过Wnt信号通路防治骨质疏松的研究进展进行了综述,以期能为相关骨代谢性疾病的预防和治疗提供新的思路。     

Wnt信号通路对骨调节研究新进展

Wnt信号通路作用于骨,主要表现为对骨组织细胞如成骨细胞、软骨细胞及破骨细胞等功能的调节。研究表明,抑制Wnt信号通路转导可使成骨细胞分化进程受阻,从而抑制骨形成;若诱导Wnt家族成员表达则可使成骨细胞特异性基因表达增加,促进骨形成。实验证实,激活Wnt信号通路对软骨细胞再生、关节形成、骨折修复都起着重要作用;Wnt信号通路在作用于成骨细胞的基础上可间接调节破骨细胞功能变化。此外,Wnt信号通路与其相关因子对骨也有调节作用。该文就Wnt信号通路对骨调节的研究进展作一综述。     

BMP2信号通路与经典Wnt信号通路及相互交联对成 骨分化的调控

在以间充质干细胞为代表的具有成骨分化潜能的细胞中,多条信号传导通路及其构成的动态调控网络参与调控其成骨分化过程。其中BMP2和经典Wnt信号通路在此过程中的作用日益受到关注。国内外研究表明,BMP2和经典Wnt信号通路在调控靶细胞成骨分化过程中伴有彼此通路中的关键分子的表达水平和功能活性的改变,并在一定条件下表现出对成骨分化特异性标志物的协同和拮抗调控。成骨增殖分化过程是一个动态过程,在成骨分化的不同阶段,分子通路的作用不同,相互之间的调节也动态变化的,研究BMP2和经典Wnt信号通路在成骨分化过程中的相互调节作用,对于指导治疗骨质疏松和骨折有重要的作用,本文就BMP2和经典Wnt信号通路对靶细胞成骨分化的调控作用以及在此过程中两条信号通路之间的交联作一简要综述。     

Rspo1通过Wnt/β-catenin信号通路调节成骨细胞分化的研究进展

在成骨细胞的分化增殖中,经典Wnt /β-catenin通路起着重要的调节作用;此通路中的任何一个因子都能影响成骨细胞的分化增殖。近几年里,大量研究证明R-脊椎蛋白家族巳成为Wnt/β-catenin信号通路的重要调节因子。本文就Rspo1通过Wnt/β-catenin信号通路调控影响成骨细胞分化增殖的研究进展作一综述。     

Wnt/β-catenin信号通路在乳腺癌中的研究进展

Wnt/β-catenin信号通路参与细胞增生分化的调节、基因表达调控和细胞迁移等重要生物过程.近年研究发现,Wnt/β-catenin信号通路的异常与乳腺癌等多种肿瘤的发生、发展密切相关.深入研究Wnt/β-catenin信号通路在乳腺癌中的作用,有助于进一步揭示乳腺癌的发生机制,为乳腺癌的防治提供新的思路及干预靶点.本文就Wnt/β-catenin通路的组成及调控机制、Wnt/β-catenin通路与乳腺癌发生、发展的关系及Wnt/β-catenin通路在乳腺癌诊治中的展望作一综述.     

力学刺激下Wnt信号通路在促进成骨分化中作用的研究进展

Wnt信号通路在骨形成过程中发挥重要作用,主要表现为对骨组织中成骨分化等功能的调节。研究表明,激活Wnt信号可增强成骨特异性基因的表达,促进骨形成;机械力学刺激在促进骨骼的发育及维持良好的骨骼形态方面具有关键作用。本文就Wnt信号通路参与力学刺激下骨向分化的调节进行综述。     

Wnt信号通路与肾细胞癌

Wnt信号是一种跨膜信号,参与细胞的分化和运动,是近年来研究的热点,针对肿瘤的许多新的分子靶向治疗亦是以Wnt信号通路为靶点的.本文就Wnt信号通路及其在肾细胞癌(RCC)中的变化、肾细胞癌中针对Wnt信号的靶向治疗作一综述.     

骨形成过程中两条重要的信号传导通路

Wnt信号通路与BMP-2信号通路能够促进成骨细胞的分化和成骨细胞分泌的胞外基质的生物矿化,在这一过程中起着极其重要的作用。本文主要综述了,近年来对这两条信号通路研究的最新进展。     

Wnt/β-catenin信号通路与骨病——作为药物靶标的潜力

分泌性蛋白家族Wnt蛋白在调节细胞生长、分化、功能及死亡等方面起着重要作用。Wnt蛋白家族激活信号时,它的经典通路Wnt/β-catenin信号通路通过一系列机制调节骨和软骨代谢,如刺激干细胞复制、促进软骨细胞成熟、诱导成骨细胞发生、阻碍成骨细胞和骨细胞凋亡等。该文就骨生物学中Wnt/β-catenin通路的研究现状、与该通路相关骨病、将该通路作为药物靶点的潜力等作一综述。     

Wnt/β-catenin信号通路与骨病——作为药物靶标的潜力

分泌性蛋白家族Wnt蛋白在调节细胞生长、分化、功能及死亡等方面起着重要作用。Wnt蛋白家族激活信号时,它的经典通路Wnt/β-catenin信号通路通过一系列机制调节骨和软骨代谢,如刺激干细胞复制、促进软骨细胞成熟、诱导成骨细胞发生、阻碍成骨细胞和骨细胞凋亡等。该文就骨生物学中Wnt/β-catenin通路的研究现状、与该通路相关骨病、将该通路作为药物靶点的潜力等作一综述。     

Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling

It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in patients with diabetes. The current study was conducted to determine the role of kallistatin in delayed wound healing in diabetic corneas. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in corneas from humans and rodents with diabetes. In murine corneal wound healing models, the canonical Wnt signaling was activated in nondiabetic corneas and suppressed in diabetic corneas, correlating with delayed wound healing. Transgenic expression of kallistatin suppressed the activation of Wnt signaling in the cornea and delayed wound healing. Local inhibition of Wnt signaling in the cornea by kallistatin, an LRP6-blocking antibody, or the soluble VLDL receptor ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of the VLDL receptor resulted in overactivation of Wnt/β-catenin signaling and accelerated corneal wound healing. Activation of Wnt signaling in the cornea accelerated wound healing. Activation of Wnt signaling promoted human corneal epithelial cell migration and proliferation, which was attenuated by kallistatin. Our findings suggested that diabetes-induced overexpression of kallistatin contributes to delayed corneal wound healing by inhibiting the canonical Wnt signaling. Thus, kallistatin and Wnt/β-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.     

Targeting the Wnt signaling pathway to augment bone formation

Recent discoveries in humans and mice have revealed that the Wnt (Wingless and Int-1) signaling pathway is responsible for a complex array of functions in maintaining bone homeostasis. The Wnt proteins are key modulators of mesenchymal lineage specification and regulate most aspects of osteoblast physiology and postnatal bone acquisition by controlling the differentiation and activity of osteoblasts and osteoclasts. Initial reports have indicated that activators of Wnt signaling are potent promoters of osteogenesis; however, systemic hyperactivation of the canonical Wnt pathway could potentially accelerate neoplastic transformation and subsequent tumor growth. Alternatively, recent investigations of natural soluble antagonists of Wnt signaling in bone suggest the possibilities of bone-specific therapies targeting the negative regulators of Wnt pathway, especially sclerostin. With this new knowledge, novel pharmacologic interventions that alter Wnt signaling are being evaluated for the management of osteoporosis. In this article, we briefly describe the Wnt signaling elements, their characterized role in bone, and summarize the current knowledge on the potential to enhance bone formation through the manipulation of Wnt signaling antagonists.     

Peptide-based mediated disruption of N-cadherin-LRP5/6 interaction promotes Wnt signaling and bone formation

Wnt signaling plays an important role in skeletal biology and diseases. In osteoblasts, we recently showed that the cell-cell adhesion molecule N-cadherin interacts with the Wnt coreceptors LRP5/6 to regulate osteogenesis. In this study we investigated whether targeting the intracellular domain of N-cadherin that interacts with LRP5/6 may promote Wnt signaling and bone formation. By investigating the molecular interactions between the Wnt coreceptors LRP5/6 and N-cadherin, we identified specific LRP5/6- and N-cadherin–interacting intracellular domains that impact Wnt/β-catenin signaling in murine osteoblasts. We showed that truncated N-cadherin constructs that impair N-cadherin-LRP5/6 interactions promote Wnt/β-catenin signaling and osteoblast differentiation. Based on this finding, we developed a peptide-based approach targeting N-cadherin-LRP5 interaction for promoting Wnt signaling and osteoblast function. We found that a competitor peptide containing the 28 last amino acids of LRP5 disrupts LRP5/6-N-cadherin interaction and thereby enhances Wnt/β-catenin signaling in osteoblasts. We also show that the peptide-mediated disruption of N-cadherin-LRP5/6 interaction increases Wnt/β-catenin signaling and osteoblast function in vitro and promotes calvaria bone formation in vivo. The targeted competitor peptide-based strategy reported here may provide a novel approach to stimulate Wnt/β-catenin signaling that can be used for promoting osteoblast function and bone formation. © 2012 American Society for Bone and Mineral Research.     

Wnt signaling in bone metabolism

A variety of in vivo models have increased understanding of the role of Wnt signaling in bone since mutations in the LRP5 gene were found in human bone disorders. Canonical Wnt signaling encourages mesenchymal progenitor cells to differentiate into osteoblasts. In osteoblasts, Wnt pathway also promotes proliferation and mineralization, while blocks apoptosis and osteoclastogenesis by increasing the OPG/RANKL ratio. Lrp6-mediated signaling in osteoblasts may regulate osteoclastogenesis. However, the role of canonical Wnt signaling in osteoclasts remains unknown, and our understanding of the role of non-canonical Wnt signaling in bone biology is also not sufficient. As to pharmacological intervention, many levels may be considered to target in Wnt signaling pathway, although tumorigenicity and toxicity to other tissues are important. Mesd might be one of target molecules to increase the quantity of LRP5/6 in the plasma membrane. Since sclerostin is almost exclusively expressed in osteocytes, abrogating sclerostin is the most promising design. T. Kubota is a recipient of JSBMR Encouragement Award of 2006.     

P120连环蛋白/转录抑制因子Kaiso与Wnt信号通路在肿瘤发病机制中的作用

异常的经典的Wnt信号通路的激活可以促进肿瘤的发生。P120连环蛋白/转录抑制因子Kaiso对Wnt信号通路的靶基因具有调控作用,影响Wnt信号通路的活动,从而影响肿瘤发生的过程。     

Wnt5a as an Effector of TGFβ in Mammary Development and Cancer

Wnt5a is a member of the Wingless-related/MMTV-integration family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories the canonical, ß-catenin-dependent pathway and the non-canonical ß-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Loss of Wnt5a is associated with early relapse of invasive breast cancer, increased metastasis, and poor survival in humans. It has been shown that TGF-ß directly regulates expression of Wnt5a in mammary gland and that Wnt5a mediates the effects of TGF-ß on branching during mammary gland development. Here we review the evidence suggesting Wnt5a acts as an effector of TGF-ß actions in breast cancer. It is suggested that the tumor suppressive functions of TGF-ß involve Wnt5a-mediated antagonism of Wnt/ß-catenin signaling and limiting the stem cell population. Interactions between TGF-ß and Wnt5a in metastasis appear to be more complex, and may depend on specific cues from the microenvironment as well as activation of specific intracellular signaling pathways.     

雌激素通过氯通道影响骨质疏松的研究进展

骨质疏松是一种严重损害老年人的疾病,而氯通道可以驱动成骨细胞的矿化、调节精细骨结构。研究发现,雌激素可激活氯通道并参与骨形成功能,提示氯通道可能是雌激素调节骨形成的重要靶点。Wnt信号通路在调节骨形成中发挥关键作用,实验表明雌激素可激活Wnt信号通路,抑制或下调Cl C-3氯通道阻断Wnt信号通路的激活,提示Cl C-3氯通道可能通过调控Wnt信号途径介导雌激素促进骨形成。该文就氯通道、雌激素及Wnt信号通路与骨质疏松关系的研究进展作一综述。     

Wnt Proteins in Mammary Development and Cancer

Secreted proteins of the Wnt family play widespread roles in the regulation of embryonic development, and aberrant activation of the canonical Wnt/beta-catenin pathway is one of the most frequent signaling abnormalities known in human cancer. While the consequences of Wnt signaling in development are diverse at the cellular level, they are often concerned with cell fate determination. Recent data also indicate that Wnt proteins influence the self-renewal of stem cells in certain tissues. In the mammary gland, Wnt signals are strongly implicated in initial development of the mammary rudiments, and in the ductal branching and alveolar morphogenesis that occurs during pregnancy. Transgenic expression of Wnt1 or Wnt10b in the mouse mammary gland leads to lobuloalveolar hyperplasia with a major risk of progression to carcinoma. Recent evidence suggests that this phenotype is associated with expansion of a multipotent progenitor cell population. In human breast cancer, evidence of beta-catenin accumulation implies that the canonical Wnt signaling pathway is active in over 50% of carcinomas. However, specific mutations that might account for this activation of signaling have not yet been identified.