Rescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics.
Rescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics.
复制标题
挽救SERCA2泵缺乏症通过塑造骨细胞钙动力学改善2型糖尿病的骨机械反应性。
DOI：
10.1038/s41467-024-45023-6
复制
发表时间：
2024-01-30
影响因子：
16.6
通讯作者：
Jing, Da
中科院分区：
文献类型：
--
作者：
Shao, Xi;Tian, Yulan;Liu, Juan;Yan, Zedong;Ding, Yuanjun;Hao, Xiaoxia;Wang, Dan;Shen, Liangliang;Luo, Erping;Guo, X. Edward;Luo, Peng;Luo, Wenjing;Cai, Jing;Jing, Da
与2型糖尿病(T2D)相关的脆性骨折是一个日益严峻的医学挑战，目前的治疗选择有限。机械负荷对于保持骨的完整性是必不可少的，尽管T2D的骨力学反应特征仍然很差。在这里，我们报告了外源性循环负荷导致的骨结构和强度的改善在遗传自发和实验诱导的T2D小鼠中都受到了损害。T2D诱导的骨力学反应的降低与骨细胞钙振荡动力学的减弱直接相关，但成骨细胞的钙振荡动力学并不依赖于PPARα介导的骨细胞SERCA2泵表达的特异性降低。SERCA2激动剂司他定的治疗通过挽救骨细胞钙动力学和成骨细胞和破骨细胞的相关调节来改善T2D骨力学反应。此外，在骨细胞SERCA2过度表达的小鼠中，T2D诱导的骨力学反应的恶化是钝化的。总而言之，我们的研究提供了对T2D介导的骨力学反应恶化的机械洞察力，并确定了一种有希望的应对T2D相关脆性骨折的对策。给你，邵某。阿尔将2型糖尿病患者的骨力学反应性降低归因于骨细胞钙动力学异常。他们发现SERCA2泵活性降低是这一过程的中介，并表明抢救SERCA2显著改善了这一背景下的骨机械适应。
Type 2 diabetes (T2D)-related fragility fractures represent an increasingly tough medical challenge, and the current treatment options are limited. Mechanical loading is essential for maintaining bone integrity, although bone mechano-responsiveness in T2D remains poorly characterized. Herein, we report that exogenous cyclic loading-induced improvements in bone architecture and strength are compromised in both genetically spontaneous and experimentally-induced T2D mice. T2D-induced reduction in bone mechano-responsiveness is directly associated with the weakened Ca2+ oscillatory dynamics of osteocytes, although not those of osteoblasts, which is dependent on PPARα-mediated specific reduction in osteocytic SERCA2 pump expression. Treatment with the SERCA2 agonist istaroxime was demonstrated to improve T2D bone mechano-responsiveness by rescuing osteocyte Ca2+ dynamics and the associated regulation of osteoblasts and osteoclasts. Moreover, T2D-induced deterioration of bone mechano-responsiveness is blunted in mice with osteocytic SERCA2 overexpression. Collectively, our study provides mechanistic insights into T2D-mediated deterioration of bone mechano-responsiveness and identifies a promising countermeasure against T2D-associated fragility fractures. Here, Shao et. al attribute the reduction in bone mechano-responsiveness seen in type 2 diabetes to abnormal osteocytic calcium dynamics. They identify reduced SERCA2 pump activity as a mediator of this process and show that rescuing SERCA2 significantly improves bone mechanical adaptation in this context.
登录
查看更多内容
影响因子：
8.1
作者：
Kersten S
通讯作者：
Kersten S
影响因子：
4.1
作者：
Jing, Da;Lu, X. Lucas;Luo, Erping;Sajda, Paul;Leong, Pui L.;Guo, X. Edward
通讯作者：
Guo, X. Edward
影响因子：
4.1
作者：
Lu, X. Lucas;Huo, Bo;Park, Miri;Guo, X. Edward
通讯作者：
Guo, X. Edward
DOI：
10.1016/j.bbrc.2004.05.035
发表时间：
2004-06-25
影响因子：
3.1
作者：
Blanquart, C;Mansouri, R;Glineur, C
通讯作者：
Glineur, C
影响因子：
4.2
作者：
Faienza MF;Pontrelli P;Brunetti G
通讯作者：
Brunetti G