Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging.
Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging.
复制标题
Cx43/miR21通路的破坏导致骨细胞凋亡和破骨细胞生成增加。
DOI：
10.1111/acel.12586
复制
发表时间：
2017-06
期刊：
影响因子：
7.8
通讯作者：
Plotkin LI
中科院分区：
文献类型：
--
作者：
Davis HM;Pacheco-Costa R;Atkinson EG;Brun LR;Gortazar AR;Harris J;Hiasa M;Bolarinwa SA;Yoneda T;Ivan M;Bruzzaniti A;Bellido T;Plotkin LI
骨老化导致骨细胞凋亡，骨细胞是嵌入骨中的细胞，其控制骨形成和再吸收细胞的产生/功能。衰老也降低了骨中连接蛋白43（Cx43）的表达;骨细胞Cx43缺失部分模拟了老年小鼠的骨骼表型。特别是，老化和Cx43缺失增加骨细胞凋亡，破骨细胞数量和骨吸收的内皮质骨表面。我们研究了衰老和Cx43缺陷引发的骨细胞凋亡和破骨细胞募集的分子信号事件。Cx43沉默的MLO-Y 4骨细胞（Cx43 def）在培养中通过caspase-3活化发生自发性细胞死亡，并表现出凋亡相关基因水平升高，只有转染能够形成间隙连接通道的Cx43构建体才能逆转Cx43 def细胞死亡。来自老年小鼠的Cx43 def细胞和骨骼表现出促存活microRNA miR 21水平降低，并且miR 21靶磷酸酶和张力蛋白同源物（PTEN）水平持续升高，磷酸化Akt水平降低，而PTEN抑制减少了Cx43 def细胞凋亡。miR 21的减少足以诱导Cx43表达细胞的凋亡，miR 21 fl/fl骨中miR 21的缺失增加了凋亡相关基因的表达，而miR 21模拟物阻止Cx43 def细胞凋亡，表明miR 21位于Cx43的下游。Cx43 def细胞释放更多的破骨细胞生成性细胞因子[NFκB配体受体激活因子（RANKL）/高迁移率族蛋白盒1（HMGB 1）]，半胱天冬酶3抑制可阻止RANKL/HMGB 1释放和Cx43 def细胞条件培养基诱导的破骨细胞生成增加，这可通过拮抗HMGB 1-κ B相互作用来阻断。这些发现确定了一种新的Cx43/miR 21/HMGB 1/RANKL通路，该通路参与预防骨细胞凋亡，也控制破骨细胞的形成/募集，并随着衰老而受损。
Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43‐silenced MLO‐Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase‐3 activation and exhibit increased levels of apoptosis‐related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro‐survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43‐expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis‐related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high‐mobility group box‐1 (HMGB1)], and caspase‐3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1‐RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.