Krishnan Venkatesh, Bryant Henry U, Macdougald Ormond A
Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana 462385, USA. krishnan_gary@lilly
J Clin Invest. 2006 May;116(5):1202-9. doi: 10.1172/JCI28551.
Wnt proteins are a family of secreted proteins that regulate many aspects of cell growth, differentiation, function, and death. Considerable progress has been made in our understanding of the molecular links between Wnt signaling and bone development and remodeling since initial reports that mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) are causally linked to alterations in human bone mass. Of the pathways activated by Wnts, it is signaling through the canonical (i.e., Wnt/beta-catenin) pathway that increases bone mass through a number of mechanisms including renewal of stem cells, stimulation of preosteoblast replication, induction of osteoblastogenesis, and inhibition of osteoblast and osteocyte apoptosis. This pathway is an enticing target for developing drugs to battle skeletal diseases as Wnt/beta-catenin signaling is composed of a series of molecular interactions that offer potential places for pharmacological intervention. In considering opportunities for anabolic drug discovery in this area, one must consider multiple factors, including (a) the roles of Wnt signaling for development, remodeling, and pathology of bone; (b) how pharmacological interventions that target this pathway may specifically treat osteoporosis and other aspects of skeletal health; and (c) whether the targets within this pathway are amenable to drug intervention. In this Review we discuss the current understanding of this pathway in terms of bone biology and assess whether targeting this pathway might yield novel therapeutics to treat typical bone disorders.
Wnt蛋白是一类分泌蛋白，可调节细胞生长、分化、功能及死亡的多个方面。自最初报道Wnt共受体低密度脂蛋白受体相关蛋白5（LRP5）的突变与人类骨量改变存在因果关系以来，我们对Wnt信号与骨骼发育和重塑之间分子联系的理解取得了相当大的进展。在Wnts激活的信号通路中，正是通过经典（即Wnt/β-连环蛋白）通路的信号传导，通过多种机制增加骨量，这些机制包括干细胞更新、刺激前成骨细胞复制、诱导成骨细胞生成以及抑制成骨细胞和骨细胞凋亡。由于Wnt/β-连环蛋白信号传导由一系列分子相互作用组成，为药物干预提供了潜在靶点，因此该通路是开发治疗骨骼疾病药物的诱人靶点。在考虑该领域合成代谢药物发现的机会时，必须考虑多个因素，包括：（a）Wnt信号在骨骼发育、重塑和病理中的作用；（b）针对该通路的药物干预如何特异性治疗骨质疏松症和骨骼健康的其他方面；以及（c）该通路中的靶点是否适合药物干预。在本综述中，我们根据骨生物学讨论对该通路的当前理解，并评估针对该通路是否可能产生治疗典型骨疾病的新型疗法。
