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lüll Wnt signaling as a therapeutic target for bone diseases Hoeppner LH; Secreto FJ; Westendorf JJExpert Opin Ther Targets 2009[Apr]; 13 (4): 485-96BACKGROUND: There is a need to develop new bone anabolic agents because current bone regeneration regimens have limitations. The Wingless-type MMTV integration site (Wnt) pathway has emerged as a regulator of bone formation and regeneration. OBJECTIVE: To review the molecular basis for Wnt pathway modulation and discuss strategies that target it and improve bone mass. METHODS: Data in peer-reviewed reports and meeting abstracts are discussed. RESULTS/CONCLUSIONS: Neutralizing inhibitors of Wnt signaling have emerged as promising strategies. Small-molecule inhibitors of glycogen synthase kinase 3beta increase bone mass, lower adiposity and reduce fracture risk. Neutralizing antibodies to Dickkopf 1, secreted Frizzled-related protein 1 and sclerostin produce similar outcomes in animal models. These drugs are exciting breakthroughs but are not without risks. The challenges include tissue-specific targeting and consequently, long-term safety.|Adaptor Proteins, Signal Transducing[MESH]|Animals[MESH]|Bone Diseases/*drug therapy/physiopathology[MESH]|Bone Morphogenetic Proteins/antagonists & inhibitors/physiology[MESH]|Bone Resorption/drug therapy[MESH]|Drug Evaluation, Preclinical[MESH]|Fractures, Bone/drug therapy[MESH]|Gene Expression Regulation/drug effects[MESH]|Genetic Markers/physiology[MESH]|Glycogen Synthase Kinase 3 beta[MESH]|Glycogen Synthase Kinase 3/antagonists & inhibitors[MESH]|Humans[MESH]|Intercellular Signaling Peptides and Proteins/deficiency/genetics/physiology[MESH]|LDL-Receptor Related Proteins/deficiency/genetics/physiology[MESH]|Low Density Lipoprotein Receptor-Related Protein-5[MESH]|Membrane Proteins/antagonists & inhibitors/deficiency/genetics/physiology[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Organ Specificity[MESH]|Osteoblasts/*drug effects/physiology[MESH]|Osteogenesis/drug effects[MESH]|Osteoporosis/drug therapy[MESH]|Protein Kinase Inhibitors/pharmacology/therapeutic use[MESH]|Regeneration/physiology[MESH]|Signal Transduction/*drug effects[MESH]|Wnt Proteins/*antagonists & inhibitors/physiology[MESH]|beta Catenin/biosynthesis/genetics[MESH] |