Osteoporosis-decreased extracellular matrix stiffness impairs connexin 43-mediated gap junction intercellular communication in osteocytes
Osteoporosis-decreased extracellular matrix stiffness impairs connexin 43-mediated gap junction intercellular communication in osteocytes
复制标题
骨质疏松症导致的细胞外基质硬度降低会损害骨细胞中连接蛋白 43 介导的间隙连接细胞间通讯
DOI：
10.1093/abbs/gmaa025
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发表时间：
2020-05-01
影响因子：
3.7
通讯作者：
Xie，Jing
中科院分区：
文献类型：
--
作者：
Zhang，Demao;Li，Xin;Xie，Jing
骨细胞是骨组织中对力学刺激的主要敏感和反应细胞。连接蛋白家族使它们能够通过形成功能性间隙连接而相互通信。然而，骨质疏松受损的细胞外机械性能如何调节骨细胞间隙连接细胞间通讯仍然是一个谜。本研究建立了卵巢切除（OVX）诱导的骨质疏松小鼠体内模型和基于聚二甲基硅氧烷（PDMS）的细胞培养基质体外模型，探讨细胞外基质（ECM）刚度对骨细胞细胞间通讯的影响。首先，我们建立了去卵巢小鼠骨质疏松模型，通过对股骨的X线、形态学和组织化学的观察来表征其变化。我们的研究结果表明，骨质疏松症降低了骨基质的刚度，同时伴有骨细胞的丢失和蛋白标志物的减少。同时，在骨质疏松小鼠中，树突状突起互连和通道形成蛋白Cx43减少。接下来，我们通过使用PDMS基质以1：5的比例对正常硬度和1：45的比例对骨质疏松症硬度进行体外模拟ECM硬度变化。我们的研究结果表明，ECM刚度降低减少了单个细胞中树突状突起的数量和相邻骨细胞之间的间隙连接。我们进一步检测到Cx43在刚度降低的基底中的表达降低。最后，我们发现，间隙连接为基础的细胞间通讯减少在活骨细胞的基板与刚度降低。本研究揭示了骨细胞外基质力学特性与细胞间通讯的相关性，为进一步从生物力学角度探讨骨质疏松症奠定了基础。
Osteocytes are the main sensitive and responsive cells for mechanical stimuli in bone. The connexin family enables them to communicate with each other via forming functional gap junctions. However, how osteoporosis-impaired extracellular mechanical property modulates gap junction intercellular communication in osteocytes remains elusive. In this study, we established an ovariectomy (OVX)-induced osteoporosis mouse modelin vivoand a polydimethylsiloxane (PDMS)-based cell culture substrate modelin vitroto explore the influence of extracellular matrix (ECM) stiffness on cell-to-cell communication in osteocytes. Firstly, we established an OVX-induced osteoporosis mouse model by characterizing the changes in radiography, morphology and histochemistry of femurs. Our results showed that osteoporosis decreased the bone matrix stiffness together with the changes including the loss of osteocytes and the decrease of protein markers. Meanwhile, the dendritic process interconnection and channel-forming protein, Cx43, were reduced in osteoporosis mice. Next we mimicked ECM stiffness changesin vitroby using PDMS substrates at ratios 1:5 for normal stiffness and 1:45 for osteoporosis stiffness. Our results showed that the decreased ECM stiffness reduced the number of dendritic processes in a single cell and gap junctions between adjacent osteocytes. We further detected the decreased expression of Cx43, in the substrate with decreased stiffness. Finally, we found that gap junction-based intercellular communication was reduced in living osteocytes in the substrate with decreased stiffness. This study demonstrates the correlation between ECM mechanical property and cell-to-cell communication in osteocytes and might pave the way for further exploration of osteoporosis in terms of biomechanics.