Osteoporosis is a systemic bone disease characterized by bone loss and bone tissue microstructure destruction (1). After the bones mature, bone formation and bone resorption are under an equilibrium, thereby maintaining normal bone mass (2). Several factors might cause the destruction of this balance and the occurrence of osteoporosis, such as aging, hormone deficiency, genetic factors, etc. (3). As the aging population grows, osteoporosis and the related complication fragility fractures result in a high disability rate. In the United States, approximately 54 million adults over the age of 50 suffer from osteoporosis or are at risk of insufficient bone mass (4). Notably, the incidence of osteoporotic fractures is about 3 to 4 times higher than that of cardiovascular disease or cancer (5). Therefore, it is of great significance to explore its molecular mechanism and develop high-efficiency treatments for osteoporosis.

Mitochondria are the unique organelles of eukaryotes, which play an important role in maintaining homeostasis, such as metabolism, energy production, oxidative stress, and apoptosis (6, 7). Osteoporosis is a prevalent aging-related disease, which is usually accompanied by changes in metabolic processes and mitochondrial dysfunction (8, 9). And mitochondrial dysfunction will lead to the accumulation of reactive oxygen species (ROS) and induce the damage of various macromolecules such as proteins, nucleic acids, and lipids in cells (10). Besides, oxidative stress could increase the activity of osteoclasts and decrease the osteogenic potential of osteoblasts, thereby destroying bone homeostasis (11–13). All these suggest that mitochondrial dysfunction might contribute to the occurrence and development of osteoporosis.

Sirtuins (SIRTs) are a family of highly conserved NAD⁺-dependent deacetylases in mammals, which influence several metabolism processes (14–16). As a member of mitochondrial sirtuins, SIRT3 is located on chromosome 11 (Chr11p15.5) and serves a critical role in mitochondrial homeostasis, metabolic regulation, gene transcription, and genome stability (17–19). SIRT3 has been reported to be involved in a variety of aging-related diseases, such as Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, and bone diseases (20, 21). A previous study showed that the senescence of bone mesenchymal stem cells (BMSCs) could lead to osteogenic damage and osteoporosis (22). And the maintenance of mitochondrial NAD⁺ levels and the expression of SIRT3 could delay the senescence of MSCs (23). Though recent evidence indicates that SIRT3 is linked to osteoporosis, the exact mechanism is still unclear. In this review, we are devoted to explaining the role and molecular mechanism of SIRT3 in osteoporosis.

In the mitochondrial sirtuins, SIRT3 exhibits strong deacetylase activity, which contains a large Rossman fold domain that binds to NAD⁺ and a small domain with a zinc finger structure (24). A large amount of evidence proves that SIRT3 could regulate mitochondrial functions from many aspects, such as energy metabolism, oxidative stress, mitophagy, etc. (25). For example, SIRT3 could deacetylate FOXO3 under the induction of hydrogen peroxide, thereby regulating mitochondrial quality, ATP production, and clearance of defective mitochondria (26).

As one of the most basic characteristics of life, energy metabolism mainly includes the release, transfer, storage, and utilization of energy. SIRT3 could promote energy production by deacetylating the subunit proteins of the mitochondrial respiratory chain complex (27). For instance, SIRT3 could maintain intracellular metabolic balance by deacetylating ATP synthase beta (28, 29). In addition, SIRT3 could deacetylate Acetyl-CoA Synthase 2, succinate dehydrogenase and 3-hydroxy-3-methylglutaryl CoA synthase 2, thereby indirectly regulating energy production (30–32). The in-vivo study also confirmed that ATP production in SIRT3^-/- mice was approximately reduced by 50% (33). In short, SIRT3 is an important regulator of energy homeostasis.

Mitochondria are not only involved in energy metabolism, but also crucial for the production and scavenging of ROS (34). A previous study showed that SIRT3 reduced the production of ROS by deacetylating FOXO3a (35). Besides, SIRT3 could increase the activity of superoxide dismutase 2 (SOD2), and result in the reduced ROS and prevention of cell senescence (36, 37). All above evidence shows that SIRT3 serves as a key mitochondrial protein to protect cells from ROS via enhancing the activity of the antioxidant defense system.

Mitophagy is a kind of mitochondrial selective autophagy, which degrades damaged mitochondria in cells (38, 39). In the myocardium of SIRT3^-/- mice, Li et al. found that SIRT3 deficiency could significantly inhibit p53/Parkin-mediated mitophagy and promote mitochondrial dysfunction (40). The deficiency in SIRT3 could also damage the mitochondrial fission and mitophagy through FOXO3a/Parkin signaling (41). Additionally, SIRT3 acts as a key activator of mitophagy, which may be mediated by the VDAC1/Parkin pathway (42). Therefore, SIRT3 is central to the maintenance of proper mitochondrial function by regulating mitophagy through multiple pathways (43).

Bone remodeling is a dynamic process including several stages: initiation/activation stage; bone resorption stage; reversal stage; osteogenesis stage; and mineralization stage (44). This process is mainly carried out in an anatomical and functional structure called basic multicellular units, involving multiple types of cells: bone stem cells, osteocytes, osteoclasts, and osteoblasts, etc. (45, 46). MSCs are a group of pluripotent stem cells developed from the mesoderm and mainly exist in the bone marrow and adipose tissue (47, 48). As the common progenitor cells of osteoblasts, adipocytes, and chondrocytes, BMSCs play an important role in bone homeostasis (49). The differentiation of BMSCs is affected by many factors, such as hormones, cytokines, and mechanical factors (49). Previous studies have shown that estrogen and bone morphogenetic protein 2 (BMP2) were the signals of the osteogenic differentiation of BMSCs, and peroxisome proliferator-activated receptor γ (PPARγ) could promote the differentiation of BMSCs into adipocytes (50, 51).

Osteoblasts are vital for bone formation, which can not only differentiate into the most abundant osteocytes but also promote the mineralization of osteoid and regulate the function of osteoclasts (52–54). Osteoclasts are multinucleated cells derived from hematopoietic stem cells and are mainly responsible for bone resorption (55). It is currently clear that nuclear factor receptor activator-B (RANK)/RANK ligand (RANKL) is the main signal pathway for osteoclast differentiation and bone resorption (56, 57). In the process of osteoclast formation, bone marrow-derived macrophages differentiate into tartrate-resistant acid phosphatase⁺ (TRAP⁺) preosteoclasts under the action of the RANKL receptor activator (58). Mononuclear preosteoclast cells fuse with each other to form multinucleated mature osteoclasts. Osteoprotegerin (OPG) is secreted by a variety of cells including osteoblasts and mainly reduces bone loss by blocking the combination of RANKL and RANK (59). The OPG levels were reduced due to the aging-related decrease of osteoblasts, thereby activating osteoclast resorption and causing osteoporosis (60). Interestingly, osteocytes, as the protagonist of bone formation, are also the main source of RANKL, thereby promoting the occurrence of osteoclasts (61). In the dynamic process of bone remodeling, all participating cells might interact or restrict each other to achieve bone homeostasis.

Osteoporosis is a chronic disease caused by the imbalance of bone formation and bone resorption (62). SIRT3 has been demonstrated to play an important role in bone remodeling. Next, we will explain how SIRT3 participates in bone remodeling and osteoporosis from different aspects, including the senescence and differentiation of BMSCs, differentiation of osteoblasts, osteoclastogenesis, and changes in bone mass ( Figure 1 ).

Accumulating evidence has indicated that intervention for SIRT3 could improve osteoporosis, showing its potential as a treatment strategy. Exogenous supplementation or overexpression of SIRT3 could alleviate bone loss and osteoporosis (75, 104). For example, the overexpression of SIRT3 by intravenous injection of recombinant adeno-associated virus 9 carrying SIRT3 plasmid (AAV9-SIRT3) could significantly reduce the occurrence of senile osteoporosis in the mouse model (75). Mild hypoxia pretreatment combined with curcumin could improve the mitochondrial function of BMSCs through PGC-1α/SIRT3/HIF-1α signal, and significantly increase cell survival (105).

Zoledronic acid is currently a common drug for the treatment of osteoporosis (106). It could enhance osteogenic differentiation of BMSCs, inhibit osteoclast activity and induce osteoclast apoptosis, thereby alleviating osteoporosis (107, 108). Recent research showed that zoledronic acid might inhibit oxidative stress through the SIRT3/SOD2 pathway to accelerate BMSCs osteogenesis and alleviate the progression of osteoporosis (109).

As an indolamine hormone and a potent free radical scavenger, melatonin could improve osteoporosis through promoting osteoblast differentiation and bone formation (110–112). Mechanism study showed that melatonin could improve mitochondrial oxidative stress through SIRT3/SOD2 signaling pathway, thereby promoting bone formation and improving bone mass loss (113, 114). Also, melatonin could inhibit oxidative damage in preosteoblasts and promote osteogenesis by activating SIRT1, which then regulates the expression of p66Shc and SIRT3 (115).

Resveratrol is a natural polyphenol found in red wine, which can inhibit osteoclast differentiation (116). Matsuda et al. found that resveratrol could alleviate dexamethasone-induced inhibition of BMP2 and OPG expression and mitochondrial dysfunction (117). Moreover, resveratrol might stimulate the SIRT3/PGC-1α/SOD2 axis by activating AMPK, thereby improving mitochondrial dysfunction and protecting osteoblasts against dexamethasone-induced cytotoxicity.

Metformin, a traditional antidiabetic drug, has been shown to have multiple efficacies in the treatment of tumors and aging (118, 119). Metformin may attenuate diabetes-related osteoporosis by improving the hyperglycemic microenvironment (120). And metformin could upregulate SIRT3 expression via PI3K/AKT pathway and reverse H₂O₂-induced osteoblast apoptosis (121).

Nevertheless, in addition to alleviating the aging of BMSCs and promoting osteogenic differentiation, it was confirmed that SIRT3 could promote osteoclast differentiation and bone resorption in aging male mice. The SIRT3 inhibitor LC-0296 was shown to increase bone mass in aging mice (100). Besides, intervention of osteoclast progenitors in 16-month-old female C57BL/6 mice with LC-0296 reduced osteoclast formation, which was consistent with the results in aged SIRT3^-/- mice. From the above-mentioned mechanism of SIRT3 in bone remodeling, the positive or negative effects of SIRT3 may be related to age and gender. In the same way, the use of upregulation and downregulation of SIRT3 to treat osteoporosis needs to be evaluated according to different situations. In the young period, SIRT3 should be upregulated to promote osteogenesis, while in the aging period, SIRT3 should be downregulated to inhibit bone resorption and alleviate osteoporosis. Of course, more animal experiments and clinical studies need to be carried out to confirm this speculation.

Osteoporosis is a common senile disease caused by a variety of factors (112). Since SIRT3 contains an N-terminal mitochondrial signal sequence, it is mainly located in the mitochondria. And SIRT3 has important implications for aging and diseases by regulating mitochondrial biology (122). In this review, SIRT3 could participate in several physiological processes including the senescence and differentiation of BMSCs, and osteoclastogenesis, thereby modulating osteoporosis. In general, SIRT3 alleviates the senescence of BMSCs by regulating oxidative stress, mitophagy, and stabilizing heterochromatin. As for the differentiation of BMSCs, osteoblastogenesis and osteoclastogenesis, the role and mechanism of SIRT3 vary with different conditions, especially age.

In conclusion, SIRT3 plays a vital role in maintaining the balance of bone formation and bone resorption. However, regarding the role of SIRT3 in bone metabolism under physiological and pathological conditions, there is still much to study.

SW contributed to the conception, design, and final approval of the submitted version. SH contributed to completing the Figure, writing the paper. The authors have read and approved the final manuscript.

The research was supported by the grant from: National Natural Science Foundation of China (81900441), Natural Science Foundation of Zhejiang Province (LQ19H020002), Zhejiang Provincial Program for Medicine and Health (2022KY446), Social Development Science and Technology Foundation of Taizhou (21ywb115, 21ywb118, 20ywb143), Social Development Science and Technology Foundation of Wenling (2020S0180083, 2021S00156, 2021S00197, 2020S0180127).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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