骨细胞 Sptbn1 基因缺陷会改变细胞存活率和机械负荷形成质膜破坏 (PMD) 后的机械传导性

IF 3.3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Mackenzie L. Hagan, Anik Tuladhar, Kanglun Yu, Dima W. Alhamad, Husam Bensreti, Jennifer Dorn, Victor M. Piedra, Nicholas Cantu, Eric G. Stokes, Daniel Blumenthal, Rachel L. Roberts, Vanshika Balayan, Sarah M. Bass, Thomas Dickerson, Anabel Liyen Cartelle, Marlian Montesinos-Cartagena, Mohamed E. Awad, Alberto A. Castro, Theodore Garland, Marion A. Cooley, Maribeth Johnson, Mark W. Hamrick, Paul L. McNeil, Meghan E. McGee-Lawrence
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引用次数: 0

摘要

我们和其他人已经证明,施加高水平的机械负荷会促进瞬时质膜破坏(PMD)的形成,从而启动机械传导。我们假设,通过破坏细胞骨架相关蛋白β2-谱蛋白(Sptbn1)来增加成骨细胞细胞膜的脆性,可能会以与PMD相关的方式改变成骨细胞的反应和骨对负荷的适应性。在 MLO-Y4 细胞中,用谱蛋白破坏剂二酰胺处理或通过 siRNA 敲除 Sptbn1 会增加流体剪切应力形成的 PMD 数量。来自骨细胞靶向 DMP1-Cre Sptbn1 条件性基因敲除(CKO)模型的原代骨细胞模拟了二硫化物和 siRNA 处理的趋势,并表明在一定程度的刺激下会形成更大的 PMD,修复速度更慢。在所有三种模型中,创伤后细胞存活都受到了影响,在 Sptbn1 CKO 培养物中,来自创伤骨细胞的钙信号反应发生了轻微改变。虽然在基线条件下,Sptbn1 CKO小鼠与WT同窝鼠相比没有表现出骨骼表型的改变,但在接受成骨性胫骨加载方案时,它们的皮质厚度增加缓慢,而且在加载2周后,有证据表明加载肢体的骨细胞死亡增加(空洞增加)。Sptbn1破坏后出现的伤口后细胞存活率降低和骨适应性减弱的现象证明,Sptbn1和PMD的形成在骨细胞机械传导和骨对机械加载的适应中发挥着重要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Osteocyte Sptbn1 Deficiency Alters Cell Survival and Mechanotransduction Following Formation of Plasma Membrane Disruptions (PMD) from Mechanical Loading

Osteocyte Sptbn1 Deficiency Alters Cell Survival and Mechanotransduction Following Formation of Plasma Membrane Disruptions (PMD) from Mechanical Loading

We and others have shown that application of high-level mechanical loading promotes the formation of transient plasma membrane disruptions (PMD) which initiate mechanotransduction. We hypothesized that increasing osteocyte cell membrane fragility, by disrupting the cytoskeleton-associated protein β2-spectrin (Sptbn1), could alter osteocytic responses and bone adaptation to loading in a PMD-related fashion. In MLO-Y4 cells, treatment with the spectrin-disrupting agent diamide or knockdown of Sptbn1 via siRNA increased the number of PMD formed by fluid shear stress. Primary osteocytes from an osteocyte-targeted DMP1-Cre Sptbn1 conditional knockout (CKO) model mimicked trends seen with diamide and siRNA treatment and suggested the creation of larger PMD, which repaired more slowly, for a given level of stimulus. Post-wounding cell survival was impaired in all three models, and calcium signaling responses from the wounded osteocyte were mildly altered in Sptbn1 CKO cultures. Although Sptbn1 CKO mice did not demonstrate an altered skeletal phenotype as compared to WT littermates under baseline conditions, they showed a blunted increase in cortical thickness when subjected to an osteogenic tibial loading protocol as well as evidence of increased osteocyte death (increased lacunar vacancy) in the loaded limb after 2 weeks of loading. The impaired post-wounding cell viability and impaired bone adaptation seen with Sptbn1 disruption support the existence of an important role for Sptbn1, and PMD formation, in osteocyte mechanotransduction and bone adaptation to mechanical loading.

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来源期刊
Calcified Tissue International
Calcified Tissue International 医学-内分泌学与代谢
CiteScore
8.00
自引率
2.40%
发文量
112
审稿时长
4-8 weeks
期刊介绍: Calcified Tissue International and Musculoskeletal Research publishes original research and reviews concerning the structure and function of bone, and other musculoskeletal tissues in living organisms and clinical studies of musculoskeletal disease. It includes studies of cell biology, molecular biology, intracellular signalling, and physiology, as well as research into the hormones, cytokines and other mediators that influence the musculoskeletal system. The journal also publishes clinical studies of relevance to bone disease, mineral metabolism, muscle function, and musculoskeletal interactions.
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