2. Academic Validation
  3. 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

  • Nat Commun. 2024 Jan 30;15(1):890. doi: 10.1038/s41467-024-45023-6.
Xi Shao # 1,  Yulan Tian # 1,  Juan Liu # 1,  Zedong Yan # 1,  Yuanjun Ding 1,  Xiaoxia Hao 1,  Dan Wang 1,  Liangliang Shen 2,  Erping Luo 1,  X Edward Guo 3,  Peng Luo 4,  Wenjing Luo 5,  Jing Cai 6,  Da Jing 7 8
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China.
  • 2 The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
  • 3 Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA.
  • 4 Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China. pengluo@fmmu.edu.cn.
  • 5 The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Fourth Military Medical University, Xi'an, China. luowenj@fmmu.edu.cn.
  • 6 College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China. 1988cai@163.com.
  • 7 Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China. jingdaasq@126.com.
  • 8 The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Fourth Military Medical University, Xi'an, China. jingdaasq@126.com.
  • # Contributed equally.
PMID: 38291059 DOI: 10.1038/s41467-024-45023-6
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.

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