The mechanotransduction of MLO-Y4 cells is disrupted by the senescence-associated secretory phenotype of neighboring cells.
The mechanotransduction of MLO-Y4 cells is disrupted by the senescence-associated secretory phenotype of neighboring cells.
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DOI：
10.1002/jcp.30690
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发表时间：
2022-04
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
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骨质疏松症相关的骨丢失是由于衰老细胞的积累及其作为衰老相关分泌表型（SASP）的一部分的炎性细胞因子的产生增加。在其他健康的个体中，骨细胞通过其响应骨骼负荷的主要功能在维持骨量方面发挥关键作用。已知骨细胞对负荷的反应随着年龄的增长而稳定下降，我们假设衰老细胞及其SASP的存在增加抑制了骨细胞对负荷的反应。为了验证这一假设，我们开发了两个体外模型的衰老骨细胞和成骨细胞来源于MLO-Y 4和MC 3 T3细胞系分别。基于细胞周期抑制剂和SASP谱的不同变化，衰老表型对于每种细胞类型是独特的。衰老骨细胞的SASP谱部分依赖于NF-κB信号传导，这为SASP在骨中的靶向作用提供了新的潜在机制。用每种衰老细胞类型的SASP培养的非衰老MLO-Y 4细胞未能表现出基因表达以及ERK磷酸化和PGE 2释放的变化。衰老骨细胞的SASP具有最大的作用，中和IL-6作为SASP的一部分恢复了骨细胞对负荷的反应。由于IL-6导致的机械转导的损失归因于P2 X7表达和对嘌呤能信号传导的总体敏感性的降低。总之，这些发现表明，衰老细胞的SASP对骨细胞的机械转导具有负面影响，并且IL-6是导致机械转导损失的关键SASP组分。
Age-related bone loss is attributed to the accumulation of senescent cells and their increasing production of inflammatory cytokines as part of the senescence associated secretory phenotype (SASP). In otherwise healthy individuals, osteocytes play a key role in maintaining bone mass through their primary function of responding to skeletal loading. Given that osteocytes’ response to loading is known to steadily decline with age, we hypothesized that the increasing presence of senescent cells and their SASP inhibit osteocytes’ response to loading. To test this hypothesis, we developed two in-vitro models of senescent osteocytes and osteoblasts derived from MLO-Y4 and MC3T3 cell lines respectively. The senescent phenotype was unique to each cell-type based on distinct changes in cell cycle inhibitors and SASP profile. The SASP profile of senescent osteocytes was in part dependent on NF-κB signaling and presents a new potential mechanism to targeting the SASP in bone. Non-senescent MLO-Y4 cells cultured with the SASP of each senescent cell-type failed to exhibit changes in gene expression as well as ERK phosphorylation and PGE2 release. The SASP of senescent osteocytes had the largest effect and neutralizing IL-6 as part of the SASP restored osteocytes’ response to loading. The loss in mechanotransduction due to IL-6 was attributed to a decrease in P2X7 expression and overall sensitivity to purinergic signaling. Altogether, these findings demonstrate that the SASP of senescent cells have a negative effect on the mechanotransduction of osteocytes and that IL-6 is a key SASP component that contributes to the loss in mechanotransduction.
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影响因子：
4.3
作者：
Hemmatian H;Bakker AD;Klein-Nulend J;van Lenthe GH
通讯作者：
van Lenthe GH
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
82.9
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.