Exercise in later life is important for bone health and delays the progression of osteoporotic bone loss. Osteocytes are the major bone cells responsible for transforming mechanical stimuli into cellular signals through their highly specialized lacunocanalicular networks (LCN). Osteocyte activity and LCN degenerate with aging, thus might impair the effectiveness of exercise on bone health; however, the underlying mechanism and clinical implications remain elusive. Herein, we showed that deletion of Sirt3 in osteocytes could impair the formation of osteocyte dendritic processes and inhibit bone gain in response to exercise in vivo. Mechanistic studies revealed that Sirt3 regulates E11/gp38 through the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. Additionally, the Sirt3 activator honokiol enhanced the sensitivity of osteocytes to fluid shear stress in vitro, and intraperitoneal injection of honokiol reduced bone loss in aged mice in a dose-dependent manner. Collectively, Sirt3 in osteocytes regulates bone mass and mechanical responses through the regulation of E11/gp38. Therefore, targeting Sirt3 could be a novel therapeutic strategy to prevent age-related bone loss and augment the benefits of exercise on the senescent skeleton.
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We thank Johan Auwerx for providing the Sirt3 floxed mice and Lynda Bonewald for providing the MLO-Y4 cell lines. We thank Dr. Cao Qian (visiting scholar from Nanjing Medical University) for helping with the animal breeding.
This work was substantially supported by Start-up grant from Chinese University of Hong Kong (Ref Nos. 4930991 and 4930992), and partly supported by the General Research Fund (Ref Nos. 14163517, 14120818 and 14104620) and Research Matching Grant Scheme, University Grants Committee, HKSAR; Health and Medical Research Fund, The Food and Health Bureau, HKSAR (Ref No. 06170546); and Area of Excellence, University Grants Committee, HKSAR (AoE/M-402/20), 2020 The American Society for Bone and Mineral Research (ASBMR) Rising Star Award, Major Project of Natural Science Foundation of China (Ref No. 81991514), Young Scientists Fund of the Natural Science Foundation of China (Ref No. 82202755), and Young Scientists Fund of the Natural Science Foundation of Jiangsu Province, China (Ref No. BK20220183).
The authors declare no competing interests.
Our studies did not include human participants or human tissue. Animal studies were approved by the Animal Experimentation Ethics Committee of The Chinese University of Hong Kong (ethical approval number 19-159-MIS).
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Edited by: M. Piacentini
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Li, Q., Wang, R., Zhang, Z. et al. Sirt3 mediates the benefits of exercise on bone in aged mice. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01053-5