Removing or truncating connexin 43 in murine osteocytes alters cortical geometry, nanoscale morphology, and tissue mechanics in the tibia.
Removing or truncating connexin 43 in murine osteocytes alters cortical geometry, nanoscale morphology, and tissue mechanics in the tibia.
复制标题
在鼠骨细胞中去除或截断连接蛋白43改变了胫骨的皮质几何形状，纳米级形态和组织力学。
DOI：
10.1016/j.bone.2016.04.021
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发表时间：
2016-07
期刊：
影响因子：
4.1
通讯作者：
Wallace JM
中科院分区：
文献类型：
--
作者：
Hammond MA;Berman AG;Pacheco-Costa R;Davis HM;Plotkin LI;Wallace JM
缝隙连接是由广泛表达的连接蛋白形成的，连接蛋白允许小信号分子在相邻细胞之间转移。缝隙连接对于骨细胞和其他骨细胞类型之间的信号传导特别重要。骨中最丰富的连接蛋白类型是连接蛋白43（Cx43）。Cx43的C端结构域被认为是间隙连接功能的重要调节剂，但该结构域在调节组织水平力学中所起的作用在很大程度上是未知的。我们假设，Cx43的C-末端结构域的缺乏将导致形态和组成的变化，以及骨如何响应参考点压痕（RPI）和断裂韧性测试的差异。在鼠模型（C57 BL/6背景）中评估了Cx43 C-末端结构域在骨细胞和其他细胞类型中的作用。将通过Cre-loxP系统去除骨细胞中内源性Cx43的小鼠与表达Cx43的敲入小鼠杂交，所述Cx43由于插入截短的等位基因而在所有细胞类型中缺乏C末端结构域，以产生研究中使用的四组。从骨细胞Cx43中去除C端结构域的主要作用是增加皮质矿物结晶度（p=0.036）和降低断裂韧性（p=0.017）。在其他细胞类型中存在C-末端结构域的主要效应是增加了小梁厚度（p<0.001）、皮质厚度（p=0.008）和平均RPI卸载斜率（p=0.004）。与对照相比，当骨细胞缺乏Cx43（p=0.008）或一些截短的Cx43在所有细胞类型中表达（p<0.001）时，胶原形态发生改变，但当骨细胞中仅表达截短形式的Cx43时，胶原形态没有改变（p=0.641）。总之，Cx43的C-末端结构域在骨细胞和其他细胞类型中的存在对于维持骨的正常结构和机械完整性是重要的。
Gap junctions are formed from ubiquitously expressed proteins called connexins that allow the transfer of small signaling molecules between adjacent cells. Gap junctions are especially important for signaling between osteocytes and other bone cell types. The most abundant type of connexin in bone is connexin 43 (Cx43). The C-terminal domain of Cx43 is thought to be an important modulator of gap junction function but the role that this domain plays in regulating tissue-level mechanics is largely unknown. We hypothesized that the lack of the C-terminal domain of Cx43 would cause morphological and compositional changes as well as differences in how bone responds to reference point indentation (RPI) and fracture toughness testing. The effects of the C-terminal domain of Cx43 in osteocytes and other cell types were assessed in a murine model (C57BL/6 background). Mice with endogenous Cx43 in their osteocytes removed via a Cre-loxP system were crossed with knock-in mice which expressed Cx43 that lacked the C-terminal domain in all cell types due to the insertion of a truncated allele to produce the four groups used in the study. The main effect of removing the C-terminal domain from osteocytic Cx43 increased cortical mineral crystallinity (p=0.036) and decreased fracture toughness (p=0.017). The main effect of the presence of the C-terminal domain in other cell types increased trabecular thickness (p<0.001), cortical thickness (p=0.008), and average RPI unloading slope (p=0.004). Collagen morphology was altered when either osteocytes lacked Cx43 (p=0.008) or some truncated Cx43 was expressed in all cell types (p<0.001) compared to controls but not when only the truncated form of Cx43 was expressed in osteocytes (p=0.641). In conclusion, the presence of the C-terminal domain of Cx43 in osteocytes and other cell types is important to maintain normal structure and mechanical integrity of bone.