High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes
High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes
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DOI：
10.1016/j.bone.2011.07.034
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发表时间：
2011-11-01
期刊：
影响因子：
4.1
通讯作者：
Robling, Alexander G.
中科院分区：
文献类型：
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作者：
Niziolek, Paul J.;Farmer, Takeisha L.;Robling, Alexander G.
参与经典Wnt信号传导途径的基因突变可导致从严重骨质疏松到严重骨质疏松的显著不同的骨骼表型。LRP 5基因中发生的许多高骨量（HBM）突变似乎部分通过增加对可溶性Wnt信号传导抑制剂（包括sclerostin）的抗性来赋予HBM表型。Sost功能丧失突变小鼠（Sost敲除）和Lrp 5功能获得突变小鼠（Lrp 5 HBM敲入）具有高骨量。这些突变体可能被预测为彼此表型相似，因为在这两种情况下，硬化素-Lrp 5相互作用被破坏。我们测量了三种不同遗传小鼠模型（Sost敲除、Lrp 5 A214 V敲入和Lrp 5 G171 V敲入）的骨质量、大小、几何形状、结构和骨强度。我们发现，所有三种小鼠品系的骨外骨骼和颅骨中的骨量均显著升高。Sost突变体和Lrp 5 A214 V突变体在大多数终点中在统计学上彼此无法区分，而两者与Lrp 5 G171 V突变体有很大不同。Lrp 5 G171 V突变体优先增加骨皮质内，而Lrp 5 A214 V和Sost突变体优先增加骨骨膜。在所有三种HBM模型中，颅骨厚度和颅神经开口发生了类似的变化。我们还评估了血清5-羟色胺水平作为一种可能的机制，占观察到的骨量变化，但血清5-羟色胺没有发现任何三个HBM小鼠系的差异。Lrp 5 G171 V突变体与其他突变体的骨骼差异表明，其他非硬化蛋白相关机制可能解释了该突变导致的骨量变化。(C)2011 Elsevier Inc. All rights reserved.
Mutations among genes that participate in the canonical Wnt signaling pathway can lead to drastically different skeletal phenotypes, ranging from severe osteoporosis to severe osteosclerosis. Many high-bone-mass (HBM) causing mutations that occur in the LRP5 gene appear to impart the HBM phenotype, in part, by increasing resistance to soluble Wnt signaling inhibitors, including sclerostin. Sost loss-of-function mutant mice (Sost knock-out) and Lrp5 gain-of-function mutant mice (Lrp5 HBM knock-in) have high bone mass. These mutants potentially would be predicted to be phenocopies of one another, because in both cases, the sclerostin-Lrp5 interaction is disrupted. We measured bone mass, size, geometry, architecture, and strength in bones from three different genetic mouse models (Sost knock-out, Lrp5 A214V knock-in, and Lrp5 G171V knock-in) of HBM. We found that all three mouse lines had significantly elevated bone mass in the appendicular skeleton and in the cranium. Sost mutants and Lrp5 A214V mutants were statistically indistinguishable from one another in most endpoints, whereas both were largely different from the Lrp5 G171V mutants. Lrp5 G171V mutants preferentially added bone endocortically, whereas Lrp5 A214V and Sost mutants preferentially added bone periosteally. Cranial thickness and cranial nerve openings were similarly altered in all three HBM models. We also assessed serum serotonin levels as a possible mechanism accounting for the observed changes in bone mass, but no differences in serum serotonin were found in any of the three HBM mouse lines. The skeletal dissimilarities of the Lrp5 G171V mutant to the other mutants suggest that other, non-sclerostin-associated mechanisms might account for the changes in bone mass resulting from this mutation. (C) 2011 Elsevier Inc. All rights reserved.