Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand
Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand
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DOI：
10.1126/scitranslmed.aau7137
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发表时间：
2018-11-07
影响因子：
17.1
通讯作者：
David, Jean-Pierre
中科院分区：
文献类型：
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作者：
Luther, Julia;Yorgan, Timur Alexander;David, Jean-Pierre
人类中的 WNT1 突变与一种新形式的成骨不全症和早发性骨质疏松症相关，这表明 WNT1 在骨量调节中发挥着关键作用。然而，Wnt1 在临床相关情况（如衰老）中的一般作用模式和治疗潜力仍有待确定。在这里，我们报告了早发性骨质疏松症患者中杂合 WNT1 突变的高患病率。我们发现成骨细胞中 Wnt1 失活会导致小鼠严重骨质疏松和自发性骨折。相比之下，成骨细胞中的条件性 Wnt1 表达通过快速增加成骨细胞数量和功能，促进发育中的幼年、成年和老年小鼠的骨量快速增加。与目前的机制模型相反，Lrp5（被认为在骨量调节过程中传递细胞外 WNT 信号的辅助受体）的缺失并没有降低 Wnt1 的骨合成代谢作用，这提供了直接证据表明 Wnt1 功能不需要 LRP5 辅助受体。 Wnt1 作为骨形成和重塑调节剂的鉴定为开发治疗骨质疏松症的 Wnt1 靶向药物奠定了基础。
WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.