Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading.
Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading.
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DOI：
10.1016/j.bone.2013.01.033
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发表时间：
2013-05
期刊：
影响因子：
4.1
通讯作者：
Yokota, Hiroki
中科院分区：
文献类型：
--
作者：
Zhao, Liming;Shim, Joon W.;Dodge, Todd R.;Robling, Alexander G.;Yokota, Hiroki
低密度脂蛋白受体相关蛋白5（Lrp 5）是Wnt信号通路中的一个辅助受体，在骨的发育和维持中起重要作用。例如，骨质疏松-假神经胶质瘤综合征是由Lrp 5的功能缺失突变引起的，而小鼠中Lrp 5的整体缺失导致骨密度显著降低。由于骨细胞被认为是骨中的机械传感器，我们提出了一个问题，即选择性骨细胞的Lrp 5（Dmp 1-Cre; Lrp 5 f/f）的功能丧失条件突变是否会改变尺骨负荷的反应。以2.65 N的峰值力对右侧尺骨施加载荷3 min（2 Hz下360次循环），连续3天，对侧尺骨用作无载荷对照。使用股骨的中段确定杨氏模量。结果表明，与年龄匹配的同窝对照组相比，骨细胞中缺乏Lrp 5的小鼠表现出较小的骨骼尺寸，骨密度和含量降低。与对照组相比，骨细胞中的Lrp 5缺失也导致杨氏模量降低4.6倍。作为对尺骨负荷的响应，骨细胞中缺乏Lrp 5的小鼠的矿化表面、矿物质沉积率和骨形成率分别减少了52%、85%和69%。总的来说，这些结果支持骨细胞中Lrp 5功能缺失突变导致机械反应性抑制并降低骨量和杨氏模量的观点。总之，Lrp 5介导的Wnt信号传导显著有助于维持机械性能和骨量。
Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of- function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre; Lrp5f/f) would alter responses to ulna loading. Loading was applied to the right ulna for 3 min (360 cycles at 2 Hz) at a peak force of 2.65 N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young’s modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young’s modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young’s modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass.
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影响因子：
5.6
作者：
Ono, Noriaki;Nakashima, Kazuhisa;Schipani, Ernestina;Hayata, Tadayoshi;Ezura, Yoichi;Soma, Kunimichi;Kronenberg, Henry M.;Noda, Masaki
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作者：
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通讯作者：
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影响因子：
64.5
作者：
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