Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone.
Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone.
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DOI：
10.1359/jbmr.081235
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Insogna KL
中科院分区：
文献类型：
--
作者：
Williams BO;Insogna KL
WNT信号已经成为骨骼建模和重塑的中央调节因子。两个Wnt共同受体LRP5和(最近)LRP6的功能丧失或功能获得突变已经引起了人们对Wnt途径在骨生物学中的重要性的关注。这篇综述总结了我们目前对Wnt通路如何作用于骨骼的理解，以及它对骨骼生理学和药物发现的影响。在过去的9年里，我们对Wnt信号的细胞靶点和这一代谢途径中的重要调节分子的理解取得了迅速的进展。规范和非规范的信号通路似乎都是重要的介导骨的WNT的影响。一个迅速扩大的基因工程小鼠目录已被用来确定下游效应分子(如β-连环蛋白)在Wnt途径中的重要性，以及Wnt信号的内源性抑制物(如Dkk1和skerostin)在骨代谢中的关键作用。事实上，骨细胞中硬化素的调节正在成为调节骨合成代谢的一条重要的最终途径，以响应各种营养刺激，从机械转导到甲状旁腺素的合成代谢作用。从一开始，人们就认为Wnt信号在骨骼中的作用是由成骨细胞前体、成骨细胞和骨细胞的直接作用引起的。然而，最近令人震惊的发现挑战了这一观点，并表明一个关键的靶点，至少在小鼠身上，是十二指肠肠嗜铬细胞。在那里，由LRP5转导的Wnt信号调节5-羟色胺的合成，而5-羟色胺以内分泌的方式调节骨细胞的代谢。将这一新信息与我们已经掌握的关于WNT在骨骼中的作用的相当多的信息进行协调需要时间。Wnt通路已迅速成为药物发现的治疗靶点。内源性Wnt抑制剂的中和抗体和小分子抑制剂已显示出作为骨合成代谢药物的早期前景。然而，鉴于Wnt通路在调节骨骼外组织生长发育中的核心作用，以及我们对这一信号级联如何实际影响骨代谢的了解仍处于初级阶段，需要做大量的工作来确保这些新疗法的安全性。
Wnt signaling has emerged as a central regulator of skeletal modeling and remodeling. Loss- or gain-of-function mutations in two Wnt co-receptors, Lrp5 and (more recently) Lrp6, have drawn attention to the importance of the Wnt pathway in bone biology. This review summarizes our current understanding of how the Wnt pathway operates on bone and the implications this has for skeletal physiology and drug discovery. Over the past 9 yr, rapid advances have been made in our understanding of the cellular targets for Wnt signaling and of the important regulatory molecules in this metabolic pathway. Both canonical and noncanonical signaling pathways seem to be important for mediating the effects of Wnt in bone. A rapidly expanding catalog of genetically engineered mice has been used to establish the importance of downstream effector molecules (such as β-catenin) in the Wnt pathway, as well as the critical role of endogenous inhibitors of Wnt signaling (such as Dkk1 and sclerostin) in bone metabolism. Indeed, regulation of sclerostin in osteocytes is emerging as an important final pathway for regulating bone anabolism in response to diverse trophic stimuli, from mechnotransduction to the anabolic actions of PTH. From the outset, it had been assumed that the effects of Wnt signaling in bone were caused by direct actions in osteoblast precursors, osteoblasts, and osteocytes. However, startling recent findings have challenged this view and suggest that a key target, at least in mice, is the duodenal enterochromaffin cell. There, Wnt signaling transduced by Lrp5 regulates serotonin synthesis, which acts in an endocrine fashion to regulate bone cell metabolism. It will take time to reconcile this new information with the considerable body of information we already have regarding the actions of Wnt in bone. The Wnt pathway has rapidly emerged as a therapeutic target for drug discovery. Neutralizing antibodies and small-molecule inhibitors of endogenous Wnt inhibitors have shown early promise as bone anabolic agents. However, given the central role of the Wnt pathway in regulating growth and development in extraskeletal tissues, as well as our still rudimentary understanding of how this signaling cascade actually affects bone metabolism, considerable work will be needed to ensure the safety of these new therapies.
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