sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss.
sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss.
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DOI：
10.1038/srep25198
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发表时间：
2016-04-27
影响因子：
4.6
通讯作者：
Kitazawa S
中科院分区：
文献类型：
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作者：
Haraguchi R;Kitazawa R;Mori K;Tachibana R;Kiyonari H;Imai Y;Abe T;Kitazawa S
sFRP 4是细胞外Wnt拮抗剂，其通过直接结合Wnt来微调其信号活性。糖尿病和衰老引起的氧化应激下的骨脆性部分与通过上调sFRP 4抑制Wnt信号有关。在这里，为了探索sFRP 4作为骨发育和重建中的平衡分子的功能，我们分析了sFRP 4基因敲入小鼠品系。sFRP 4-LacZ杂合子小鼠在新生儿和出生后阶段的股骨骨干的限制区域，主要是在成骨细胞和破骨细胞中，可检测到X-gal和荧光化学染色信号。组织学和μCT分析显示，sFRP 4突变体的骨小梁质量增加，Wnt信号和成骨活性改变;这增强了老化期间骨小梁形成的影响。我们的研究结果表明sFRP 4通过调节成骨细胞和破骨细胞在骨发育和重塑中起着关键作用，并且其功能丧失可防止骨小梁区域中与年龄相关的骨丢失。这些发现意味着sFRP 4作为Wnt信号通路的关键潜在内源性平衡物，通过在骨骼骨发育和通过重塑维持期间有效地对骨形成和骨吸收两者具有直接影响。
sFRP4 is an extracellular Wnt antagonist that fine-tunes its signal activity by direct binding to Wnts. Bone fragility under oxidative stress by diabetes and aging is partly related to the suppression of the Wnt signal through upregulated sFRP4. Here, to explore the functions of sFRP4 as a balancer molecule in bone development and remodeling, we analyzed the sFRP4 knock-in mouse strain. X-gal and immunohistochemically stained signals in sFRP4-LacZ heterozygous mice were detectable in restricted areas, mostly in osteoblasts and osteoclasts, of the femoral diaphysis after neonatal and postnatal stages. Histological and μCT analyses showed increased trabecular bone mass with alteration of the Wnt signal and osteogenic activity in sFRP4 mutants; this augmented the effect of the buildup of trabecular bone during the ageing period. Our results indicate that sFRP4 plays a critical role in bone development and remodeling by regulating osteoblasts and osteoclasts, and that its functional loss prevents age-related bone loss in the trabecular bone area. These findings imply that sFRP4 functions as a key potential endogenous balancer of the Wnt signaling pathway by efficiently having direct influence on both bone formation and bone absorption during skeletal bone development and maintenance through remodeling.