Rescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics

Xi Shao, Yulan Tian, Juan Liu, Zedong Yan, Yuanjun Ding, Xiaoxia Hao, Dan Wang, Liangliang Shen, Erping Luo, X. Edward Guo, Peng Luo (), Wenjing Luo (), Jing Cai () and Da Jing ()
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Xi Shao: Fourth Military Medical University
Yulan Tian: Fourth Military Medical University
Juan Liu: Fourth Military Medical University
Zedong Yan: Fourth Military Medical University
Yuanjun Ding: Fourth Military Medical University
Xiaoxia Hao: Fourth Military Medical University
Dan Wang: Fourth Military Medical University
Liangliang Shen: Fourth Military Medical University
Erping Luo: Fourth Military Medical University
X. Edward Guo: Columbia University
Peng Luo: Xijing Hospital, Fourth Military Medical University
Wenjing Luo: Fourth Military Medical University
Jing Cai: Shaanxi University of Chinese Medicine
Da Jing: Fourth Military Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45023-6

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