Antagonists of LRP6 regulate PTH-induced cAMP generation
Antagonists of LRP6 regulate PTH-induced cAMP generation
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LRP6 拮抗剂调节 PTH 诱导的 cAMP 生成
DOI：
10.1111/j.1749-6632.2011.06226.x
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Wan, Mei
中科院分区：
文献类型：
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作者：
Shi, Chenhui;Li, Jun;Wan, Mei
LRP 6是不同G蛋白偶联的七跨膜受体在cAMP产生中的共同核心受体。细胞外蛋白sclerostin和DKK 1最初被鉴定为通过与LRP 6结合的Wnt信号传导的拮抗剂，是骨形成的负调节剂。在这里，我们表明，硬化素和DKK 1抑制PTH刺激的cAMP的生产。此外，PTH抑制小鼠骨细胞中硬化蛋白的表达。我们还发现，sclerostin和DKK 1作为拮抗剂与LRP 6结合，以增加LRP 6的可用性，从而以正反馈方式促进PTH信号传导。这些研究揭示了sclerostin和DKK 1以前未被认识到的功能，这为sclerostin和DKK 1中和在增强骨形成方面的应用提供了另一种解释，作为骨骼疾病的潜在疗法。
LRP6 is a common coreceoptor for different G protein-coupled seven-transmembrane receptors in production of cAMP. Extracelluar proteins sclerostin and DKK1, initially identified as antagonists for Wnt signaling by binding to LRP6, are negative regulators for bone formation. Here, we show that both sclerostin and DKK1 inhibit PTH-stimulated cAMP production. In addition, PTH suppresses expression of sclerostin in osteocytes in mice. We also found that sclerostin and DKK1 binds to LRP6 as antagonists to increase the availability of LRP6 to facilitate PTH signaling in a positive-feedback fashion. These studies reveal a previously unrecognized function of sclerostin and DKK1, which provides an alternative explanation for the application of sclerostin and DKK1 neutralization on enhancing bone formation as a potential therapy for skeletal diseases.