TITLE:
Bidirectional Role of Sirt3 in Bone Metabolism Regulation and Translational Research Progress
AUTHORS:
Rongxin Meng, Taoxian Wang, Shengchao Yang, Junxiang Wang, Cheng Peng, Dinggui Lu
KEYWORDS:
Sirt3, Osteogenic Differentiation, Mitochondria, sENP3-DLX2 Axis, Bone Immunity, Osteoporosis
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.14 No.7,
July
6,
2026
ABSTRACT: Sirt3 is a mitochondrial NAD+-dependent deacetylase whose downregulation is closely associated with osteoporosis, yet its complete mechanism of action and upstream signals remain unclear. This review systematically integrates in vitro and in vivo studies on the role of Sirt3 in bone metabolism, covering dimensions such as direct regulation, immuno-osteogenic coupling, upstream transcriptional control, and functional bidirectionality. Sirt3 maintains mitochondrial oxidative stress homeostasis by deacetylating SOD2 and FOXO3a, promotes energy metabolism and mitophagy, and positively regulates BMSC osteogenic differentiation. It also orchestrates an “mitochondria-immune-osteogenesis” interactive network by reprogramming M1/M2 polarization of macrophages. SENP3 activates Sirt3 transcription by deSUMOylating DLX2, establishing a novel upstream regulatory axis. However, Sirt3 function exhibits marked cell type- and age-dependence—it can promote bone resorption or degeneration in osteoclasts and chondrocytes, respectively, and under aging conditions its activity declines with NAD+ depletion, leading to an imbalance between osteogenic and adipogenic differentiation. Although Sirt3 regulates bone metabolism through a multi-layered network, its functional polarity is codetermined by NAD+ availability, oxidative stress, and upstream modifications. This review aims to move beyond the conventional view of Sirt3 as a mere “pro-bone” factor, offering new targets for individualized treatment of osteoporosis and emphasizing the need for precision intervention strategies tailored to cell type, age, and pathological microenvironment.