Hoeppner Luke H, Secreto Frank J, Westendorf Jennifer J
Graduate Program in Microbiology, Immunology and Cancer Biology, University of Minnesota, Minneapolis, MN, USA.
Expert Opin Ther Targets. 2009 Apr;13(4):485-96. doi: 10.1517/14728220902841961.
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.
To review the molecular basis for Wnt pathway modulation and discuss strategies that target it and improve bone mass.
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.
由于目前的骨再生方案存在局限性，因此需要开发新的骨合成代谢药物。无翅型MMTV整合位点（Wnt）信号通路已成为骨形成和再生的调节因子。
综述Wnt信号通路调节的分子基础，并讨论靶向该通路并增加骨量的策略。
讨论同行评审报告和会议摘要中的数据。
结果/结论：Wnt信号的中和抑制剂已成为有前景的策略。糖原合酶激酶3β的小分子抑制剂可增加骨量、降低肥胖程度并降低骨折风险。针对Dickkopf 1、分泌型卷曲相关蛋白1和硬化蛋白的中和抗体在动物模型中产生类似结果。这些药物是令人兴奋的突破，但并非没有风险。挑战包括组织特异性靶向以及因此产生的长期安全性问题。
