Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts
Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts
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DOI：
10.1172/jci69443
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发表时间：
2013-09-01
影响因子：
15.9
通讯作者：
Jones, Dallas C.
中科院分区：
文献类型：
--
作者：
Shim, Jae-Hyuck;Greenblatt, Matthew B.;Jones, Dallas C.
缺乏Schnurri-3（SHN 3;也称为HIVEP 3）的小鼠显示骨形成增加，但利用这一观察结果获得治疗益处需要更好地了解SHN 3如何在成骨细胞中发挥作用。在这里，我们确定SHN 3作为ERK活性的损伤因子，其在成骨细胞中的WNT信号传导的下游部分起作用。SHN 3内的D-结构域基序介导ERK活性和成骨细胞分化的相互作用和抑制，并且敲入消除这种相互作用的Shn 3中的突变导致异常ERK激活和随后的成骨细胞体内过度活跃。此外，体内遗传相互作用研究表明，与Lrp 5（-/-）小鼠杂交部分挽救了Shn 3（-/-）小鼠的成骨细胞表型;从机制上讲，这对应于SHN 3抑制ERK介导的GSK 3 β抑制的能力。成年小鼠中Shn 3的诱导性敲低导致高骨量表型，这提供了证据表明，在成年人中短暂阻断这些途径有望成为骨质疏松症的治疗方法。
Mice deficient in Schnurri-3 (SHN3; also known as HIVEP3) display increased bone formation, but harnessing this observation for therapeutic benefit requires an improved understanding of how SHN3 functions in osteoblasts. Here we identified SHN3 as a dampener of ERK activity that functions in part downstream of WNT signaling in osteoblasts. A D-domain motif within SHN3 mediated the interaction with and inhibition of ERK activity and osteoblast differentiation, and knockin of a mutation in Shn3 that abolishes this interaction resulted in aberrant ERK activation and consequent osteoblast hyperactivity in vivo. Additionally, in vivo genetic interaction studies demonstrated that crossing to Lrp5(-/-) mice partially rescued the osteosclerotic phenotype of Shn3(-/-) mice; mechanistically, this corresponded to the ability of SHN3 to inhibit ERK-mediated suppression of GSK3 beta. Inducible knockdown of Shn3 in adult mice resulted in a high-bone mass phenotype, providing evidence that transient blockade of these pathways in adults holds promise as a therapy for osteoporosis.