Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice
Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice
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DOI：
10.1073/pnas.0505259102
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发表时间：
2005-11-29
影响因子：
11.1
通讯作者：
Rawadi, G
中科院分区：
文献类型：
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作者：
Clément-Lacroix, P;Ai, MR;Rawadi, G
锂的一个很好的细胞生物学作用是抑制糖原合成酶-3β，从而激活典型的Wnt信号。由于Wnt信号缺陷与骨量减少的疾病有关，我们测试了锂是否可以改善小鼠的骨量。我们用三种不同品系(LRP5(-/-)、SAMP6和C57BL/6)的氯化锂灌胃给8周龄的小鼠，并在治疗4周后评估其对骨代谢的影响。LRP5(-/-)小鼠缺乏Wnt共同受体低密度脂蛋白受体相关蛋白5，并显著减少骨量。锂被预测作用于该受体的下游，使这些小鼠的骨代谢和骨量恢复到接近野生型的水平。SAMP6小鼠由于成骨细胞更新不足而加速骨质疏松。锂显著改善了这些小鼠和野生型C57BL/6小鼠的骨量。我们发现锂激活了体外培养的LRP5(-/-)小鼠颅骨成骨细胞中典型的Wnt信号，并且在体内，锂处理的小鼠的骨髓细胞中Wnt反应基因的表达增加。这些数据使我们得出结论，锂可以促进小鼠的骨形成和改善骨量，而且它可能是通过激活规范的WRIT途径来实现这一点的。半个多世纪以来，锂一直被安全有效地用于治疗双相情感障碍。在接受锂治疗的患者中进行的前瞻性研究应该确定它是否也能改善人类的骨量。
one of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3 beta and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains (Lrp5(-/-), SAMP6, and C57BL/6) and assessed the effect on bone metabolism after 4 weeks of therapy. Lrp5(-/-) mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL/6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from Lrp5(-/-) mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Writ pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans.