Osteoporosis and bone fractures are global health problems. Identification of new therapeutic targets and strategies are of paramount importance. Signaling by the Wnt family of secreted proteins has emerged as a key pathway for human bone mass regulation, as loss-of-function and 'gain-of-function'mutations in Wnt coreceptor LRP5 are associated with familial osteoporosis and high bone mass diseases, respectively. Wnt/LRP5 signaling primarily regulates the osteoblast lineage and bone generation, providing a potential avenue for therapeutics that stimulates bone growth. Remarkably secreted Wnt antagonists are expressed in bone and modulate Wnt/LRP5 signaling locally, and thus offer treatment opportunities targeting bone specifically. Indeed Sclerostin, an osteocyte-specific secreted factor that binds to and inhibits LRP5, has become a key drug target for osteoporosis. We have identified a new family of Wnt antagonists, referred to as Tiki proteins, which likely are novel enzymes that post-translationally modify and inactivate Wnt ligands. We have generated Tiki2-/- mutant mice, which surprisingly are viable but exhibit high bone mass, suggesting that Tiki2, like Sclerostin, is an important negative regulator of bone homeostasis. Because of its enzymatic activity human TIKI2 may be an ideal target for small molecule inhibitors for potential therapeutic intervention for osteoporosis. We propose four aims to investigate the role of Tiki2 in bone biology and potential therapeutic implications.
In Aim 1, we will characterize the high bone mass phenotype of Tiki2-/- mutant mice, employing histological, biochemical and biomechanical methods. We will also examine in details the expression of Tiki2 in bone cell types, its regulation in bone by anabolic and mechanical stimuli.
In Aim 2, we will generate mutant mice with conditional Tiki2 deletion in the bone and in the adulthood via cell type- specific and a tamoxifen-inducible Cre lines. These studies will define the site and stage of Tiki2 action in bone and in the aging process.
In Aim 3, we will investigate human TIKI2 (and TIKI1) bone-related functions and biochemical properties in vitro. We will investigate TIKI2 and TIKI1 expression in bone, and study whether TIKI2 and TIKI1 regulates bone formation in human osteoblast-like cell lines, and characterize the specific Wnt proteins that are modified/inactivated by TIKI proteins in bone mass regulation.
In Aim 4, we will identify small molecule inhibitors of TIKI2 via chemical compound screening and to evaluate their potential in bone growth stimulation in vitro and in vivo. As a new class of Wnt antagonists with an enzymatic activity, TIKI proteins are ideal targets for small molecule inhibitors for use in experimental manipulation and therapeutic intervention. We will perform a high throughput chemical compound screen to identify Tiki2 inhibitors for their potential applications in stimulating bone growth. These studies together represent a comprehensive analysis of TIKI function in bone biology via genetic, biochemical and chemical biological methods, and may discover potential novel therapeutics for osteoporosis and bone regeneration.
Cell-to-cell communication is vital for human bone mass regulation. Defects in these communication networks underlie bone diseases including osteoporosis. We have identified a new gene, called TIKI2, which may regulate cell communication in bone growth. This proposal aims to understand how TIKI2 regulates bone development and growth in the mouse model and human cells, and to search for chemical inhibitors for TIKI2 for potential use in bone growth stimulation. These studies will likely provide better understanding of human bone biology, and may identify new therapeutic strategies and molecules for potential treatment of osteoporosis and bone fractures.
|Zhang, Xinjun; MacDonald, Bryan T; Gao, Huilan et al. (2016) Characterization of Tiki, a New Family of Wnt-specific Metalloproteases. J Biol Chem 291:2435-43|
|Niziolek, Paul J; MacDonald, Bryan T; Kedlaya, Rajendra et al. (2015) High Bone Mass-Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo. J Bone Miner Res 30:1822-30|
|MacDonald, Bryan T; Hien, Annie; Zhang, Xinjun et al. (2014) Disulfide bond requirements for active Wnt ligands. J Biol Chem 289:18122-36|
|Guo, Chaoshe; Sun, Ye; Guo, Chunming et al. (2014) Dkk1 in the peri-cloaca mesenchyme regulates formation of anorectal and genitourinary tracts. Dev Biol 385:41-51|
|Reis, Alice H; Macdonald, Bryan T; Feistel, Kerstin et al. (2014) Expression and evolution of the Tiki1 and Tiki2 genes in vertebrates. Int J Dev Biol 58:355-62|
|Kim, Sung-Eun; Huang, He; Zhao, Ming et al. (2013) Wnt stabilization of Î²-catenin reveals principles for morphogen receptor-scaffold assemblies. Science 340:867-70|
|Bazan, J Fernando; Macdonald, Bryan T; He, Xi (2013) The TIKI/TraB/PrgY family: a common protease fold for cell signaling from bacteria to metazoa? Dev Cell 25:225-7|
|Zhang, Xinjun; He, Xi (2013) PAF makes it EZ(H2) for *-catenin transactivation. Mol Cell 52:157-8|
|De Robertis, Alessandra; Valensin, Silvia; Rossi, Marco et al. (2013) Identification and characterization of a small-molecule inhibitor of Wnt signaling in glioblastoma cells. Mol Cancer Ther 12:1180-9|
|Macaulay, Iain C; Thon, Jonathan N; Tijssen, Marloes R et al. (2013) Canonical Wnt signaling in megakaryocytes regulates proplatelet formation. Blood 121:188-96|
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