Journal
EMBO MOLECULAR MEDICINE
Volume 8, Issue 4, Pages 375-387Publisher
WILEY
DOI: 10.15252/emmm.201505714
Keywords
CXXC5; Dishevelled; negative feedback regulation; osteoporosis; Wnt/beta-catenin pathway
Categories
Funding
- Ministry of Future Creation and Science (MFCS) of Korea through National Research Foundation (NRF)
- Translational Research Center for Protein Function Control [2009-0083522]
- Mid-career Researcher Program [2015R1A2A1A05001873]
- Ministry of Knowledge Economy through Korea Research Institute of Chemical Technology [SI-0905, SI-1005, SI-1105, SI-1205, SI-1304]
- National Research Council of Science & Technology (NST), Republic of Korea [SI-1205, SI-0905, SI-1005, SI-1304, SI-1105] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Bone anabolic agents promoting bone formation and rebuilding damaged bones would ideally overcome the limitations of anti-resorptive therapy, the current standard prescription for osteoporosis. However, the currently prescribed parathyroid hormone (PTH)-based anabolic drugs present limitations and adverse effects including osteosarcoma during long-term use. Also, the antibody-based anabolic drugs that are currently being developed present the potential limits in clinical application typical of macromolecule drugs. We previously identified that CXXC5 is a negative feedback regulator of the Wnt/-catenin pathway via its interaction with Dishevelled (Dvl) and suggested the Dvl-CXXC5 interaction as a potential target for anabolic therapy of osteoporosis. Here, we screened small-molecule inhibitors of the Dvl-CXXC5 interaction via a newly established invitro assay system. The screened compounds were found to activate the Wnt/-catenin pathway and enhance osteoblast differentiation in primary osteoblasts. The bone anabolic effects of the compounds were shown using exvivo-cultured calvaria. Nuclear magnetic resonance (NMR) titration analysis confirmed interaction between Dvl PDZ domain and KY-02061, a representative of the screened compounds. Oral administration of KY-02327, one of 55 newly synthesized KY-02061 analogs, successfully rescued bone loss in the ovariectomized (OVX) mouse model. In conclusion, small-molecule inhibitors of the Dvl-CXXC5 interaction that block negative feedback regulation of Wnt/-catenin signaling are potential candidates for the development of bone anabolic anti-osteoporosis drugs.
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