The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations
The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations
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DOI：
10.1007/s00223-008-9130-9
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发表时间：
2008-06-01
影响因子：
4.2
通讯作者：
Van Hul, Wim
中科院分区：
文献类型：
--
作者：
Balemans, Wendy;Piters, Elke;Van Hul, Wim
低密度脂蛋白受体相关蛋白5(LRP5)是一种Wnt辅助受体，其功能缺失和功能获得突变分别导致常染色体隐性骨质疏松症-假性胶质瘤综合征和无染色体显性高骨量(HBM)表型，在骨代谢中起重要作用。先前的研究表明，HBM相关的LRP5突变的存在会导致LRP5介导的Wnt信号的拮抗性降低。在本研究中，我们研究了六种不同的HBM-LRP5突变，证实Dickkopfl(DKKI)和skerostin都不能有效地抑制HBM-LRP5信号转导。此外，当共表达时，DKKI和硬化素对HBM-LRP5突变体的抑制作用并不比单独使用任何一种抑制剂更好。此外，DKKI和硬化素不同时与野生型LRP5结合，DKKI能够取代先前形成的硬化素-LRP5复合体中的硬化素。综上所述，我们的结果表明Dkk1和skerostin对LRP5信号的调节是独立的，而不是协同的，并且它们的功能都受到HBM-LRP5突变的影响。
Low-density lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor, plays an important role in bone metabolism as loss-of-function and gain-of-function mutations in LRP5 result in the autosomal recessive osteoporosis-pseudoglioma syndrome and amosomal dominant high-bone mass (HBM) phenotypes, respectively. Prior studies suggested that the presence of HBM-associated LRP5 mutations results in decreased antagonism of LRP5mediated Wnt signaling. In the present study, we investigated six different HBM-LRP5 mutations and confirm that neither Dickkopfl (DKKI) nor sclerostin efficiently inhibits HBM-LRP5 signaling. In addition, when coexpressed, DKKI and sclerostin do not inhibit HBM-LRP5 mutants better than either inhibitor by itself. Also, DKKI and sclerostin do not simultaneously bind to wild-type LRP5, and DKKI is able to displace sclerostin from previously formed sclerostin-LRP5 complexes. In conclusion, our results indicate that DKK1 and sclerostin are independent, and not synergistic, regulators of LRP5 signaling and that the function of each is impaired by HBM-LRP5 mutations.