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, Da Jing
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 Ca 2+ 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 Ca 2+ 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.