The Therapeutic Potential of the Wnt Signaling Pathway in Bone Disorders

Liang      Chen; Tong-Chuan      He; Rex      C. Haydon; Hue      H. Luu; Russell      R. Reid; Zhong-Liang      Deng; Jiayi      Huang; Xiaoji      Luo; Jinyong      Luo; Yuxi      Su; Yang      Bi; Guo-Wei      Zuo; Eric      R. Wagner; Bai-Cheng      He; Ke      Yang; Farbod      Rastegar; Stephanie      H. Kim; Jian-Li      Gao; Yanhong      Gao; Enyi      Huang; Qiong      Shi; Qing      Luo; Bing-Qiang      Zhang; Gaohui      Zhu

Abstract

The Wnt pathway plays a critical role in development and differentiation of many tissues, such as the gut, hair follicles, and bone. Increasing evidence indicates that Wnts may function as key regulators in osteogenic differentiation of mesenchymal stem cells and bone formation. Conversely, aberrant Wnt signaling is associated with many osteogenic pathologies. For example, genetic alterations in the Wnt signaling pathway lead to osteoporosis and osteopenia, while inactivating mutations of Wnt inhibitors result in a hyperostotic skeleton with increased bone mineral density. Hyperparathyroidism causes osteopenia via induction of the Wnt signaling pathway. Lithium, often used to treat bipolar disorder, blocks a Wnt antagonist, decreasing the patient's risk of fractures. Thus, manipulating the Wnt pathway may offer plenty therapeutic opportunities in treating bone disorders. In fact, induction of the Wnt signaling pathway or inhibition of Wnt antagonists has shown promise in treating bone metabolic disorders, including osteoporosis. For example, antibodies targeting the Wnt inhibitor Sclerostin lead to increased bone mineral density in post-menopausal women. However, such therapies targeting the Wnt pathway are not without risk, as genetic alternations may lead to over-activation of Wnt/β- catenin and its association with many tumors. It is conceivable that targeting Wnt inhibitors may predispose the individuals to tumorigenic phenotypes, at least in bone. Here, we review the roles of Wnt signaling in bone metabolic and pathologic processes, as well as the therapeutic potential for targeting Wnt pathway and its associated risks in bone diseases.

Keywords: Wnt, osteoporosis, sclerostin, catenin, osteogenesis, fracture, osteogenic differentiation, LRP5/6, osteopenia, post-menopausal, cell proliferation, apoptosis, tumorigenesis, FAP, glycoproteins, Frz, stabilization, translocation, GSK3, transcription, c-Myc, cyclin D1, PPAR, APC, PKC, Elk-1, CaCN, NF-AT, phospholipase c, IP3, Dkk-1, SFRPs, Gleevec, Adipogenesis, transducers, antagonists, WIFs, Krm 1/2, Sost, Krm, T-lymphoid, MSCs, BMPs, Hh, Src/ERK, PI3K/Akt, LRP5, OPPG, mutations, osteblasts, Tcf1, bone mass, phenotypes, SERMs, Antibodies, Axin, DCA, BIO, parathyroid hormone, TUMORIGENIC, osteosarcoma, WIF1