β-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice.
β-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice.
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DOI：
10.1002/jbmr.1834
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发表时间：
2013-05
影响因子：
6.2
通讯作者：
Long, Fanxin
中科院分区：
文献类型：
--
作者：
Chen, Jianquan;Long, Fanxin
关键词：
小鼠遗传学研究表明 β-连环蛋白在骨骼中发挥多种作用。在胚胎中，β-连环蛋白对于成骨细胞分化的早期阶段至关重要。出生后，成熟成骨细胞和骨细胞中的β-连环蛋白间接抑制破骨细胞分化。然而，β-连环蛋白在调节成骨细胞数量和/或功能（特别是在出生后）中的直接作用尚未得到证实。解决这一知识空白非常重要，因为 LRP5（一种 WNT 信号传导的共同受体，被认为通过 β-连环蛋白发挥作用）控制出生后小鼠或人类的成骨细胞数量和功能。为了克服早期成骨细胞谱系细胞中β-连环蛋白的胚胎缺失引起的新生儿致死率，我们利用Osx-CreERT2通过给出生后小鼠暂时施用他莫昔芬（TM）来去除Osx表达细胞中的β-连环蛋白。长骨中的谱系追踪实验表明，Osx-CreERT2 主要针对骨表面的成骨细胞谱系细胞，但也针对有助于骨髓基质细胞和脂肪细胞的瞬时祖细胞。通过这种策略删除β-连环蛋白大大降低了目标成骨细胞的骨形成活性。然而，目标成骨细胞迅速转变并被过量的非目标成骨细胞取代，导致骨形成意外增加，但破骨细胞数量和活性的更大增加会产生严重骨质减少的净效应。随着时间的推移，突变小鼠的骨髓脂肪也显着增加。因此，出生后 Osx 谱系细胞中的 β-连环蛋白通过促进成骨细胞活性和抑制成骨细胞更新来关键调节骨稳态，同时抑制破骨细胞和骨髓脂肪形成。
Genetic studies in the mouse have demonstrated multiple roles for β-catenin in the skeleton. In the embryo, β-catenin is critical for the early stages of osteoblast differentiation. Postnatally, β-catenin in mature osteoblasts and osteocytes indirectly suppresses osteoclast differentiation. However, a direct role for β-catenin in regulating osteoblast number and/or function specifically in the postnatal life has not been demonstrated. Addressing this knowledge gap is important because LRP5, a co-receptor for WNT signaling proposed to function through β-catenin, controls osteoblast number and function in postnatal mice or humans. To overcome the neonatal lethality caused by embryonic deletion of β-catenin in early-stage osteoblast-lineage cells, we utilize Osx-CreERT2 to remove β-catenin in Osx-expressing cells by administering tamoxifen (TM) temporarily to postnatal mice. Lineage-tracing experiments in the long bones demonstrate that Osx-CreERT2 targets predominantly osteoblast-lineage cells on the bone surface, but also transient progenitors that contribute to bone marrow stromal cells and adipocytes. Deletion of β-catenin by this strategy greatly reduces the bone formation activity of the targeted osteoblasts. However, the targeted osteoblasts rapidly turn over and are replaced by an excessive number of non-targeted osteoblasts, causing an unexpected increase in bone formation, but an even greater increase in osteoclast number and activity produces a net effect of severe osteopenia. With time, the mutant mice also exhibit a marked increase in bone marrow adiposity. Thus, β-catenin in postnatal Osx-lineage cells critically regulates bone homeostasis by promoting osteoblast activity and suppressing osteoblast turnover, while restraining osteoclast and marrow fat formation.
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影响因子：
82.9
作者：
通讯作者：
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影响因子：
2.7
作者：
Joeng KS;Schumacher CA;Zylstra-Diegel CR;Long F;Williams BO
通讯作者：
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作者：
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通讯作者：
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通讯作者：
de Crombrugghe, B
影响因子：
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作者：
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通讯作者：
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