Curcumin activates SIRT3 to protect bone structure in diabetic mice

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Aug 13 2025

New research shows how curcumin’s molecular power protects bone cells from high-glucose stress, repairs mitochondria, and boosts antioxidant defences, offering hope for tackling diabetes-related bone loss.

Study: Curcumin preserves bone health compromised by diabetes by inhibiting osteoporosis through regulation of the SIRT3/FoxO3a signalling pathway. Image Credit: Anicka S / Shutterstock

In a recent study published in the journal Scientific Reports, researchers tested whether curcumin counteracts diabetic osteoporosis by activating Sirtuin-3 (SIRT3)/Forkhead box protein O3a (FoxO3a) signaling and the downstream antioxidant protein network including nuclear factor erythroid 2-related factor 2 (NRF2) and its target NAD(P)H:quinone oxidoreductase 1 (NQO1) to curb mitochondrial oxidative stress and restore osteoblast differentiation in vitro, with corresponding gains in bone microarchitecture in vivo.

Background

One in two older adults will deal with fragile bones, and many also live with type 2 diabetes mellitus (T2DM), which is a tough combination that raises fracture risk and slows healing. Diabetic osteoporosis is driven by chronic hyperglycemia, high reactive oxygen species (ROS), and sluggish osteoblast activity, leading to falls, hospital stays, and rising costs.

Standard osteoporosis drugs often underperform in T2DM, and few treatments directly fix the mitochondrial dysfunction that fuels ROS damage in bone cells. Nutritional polyphenols like curcumin are widely used and generally safe, but their bone-specific actions under hyperglycemia are not fully mapped. More research is needed to pinpoint mitochondrial targets, confirm protective pathways, and fine-tune dosing for real-world benefit.

The authors also note that curcumin’s mechanism may link mitochondrial regulation to epigenetic control of osteogenic genes, adding another potential therapeutic layer.

About the study

Mouse osteoblasts (MC3T3-E1 cell line) were cultured in Minimum Essential Medium alpha (α-MEM) with 10% fetal bovine serum (FBS) at 37 °C under 5% carbon dioxide (CO₂). To simulate T2DM, cells were exposed to high glucose (25.5 mM) for 24 h, then treated with curcumin (0, 1, 10, 100 μM) for 48 h. The middle concentration (10 μM) showed the strongest protective effect, whereas 1 μM and 100 μM were less effective, suggesting a bell-shaped dose–response pattern.

Cell viability was measured using Cell Counting Kit-8 (CCK-8).

Mitochondrial ultrastructure was assessed by transmission electron microscopy (TEM), and mitochondrial membrane potential by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) flow cytometry. Intracellular ROS were quantified with 2′,7′-dichlorofluorescin diacetate (DCFH-DA). Malondialdehyde (MDA), superoxide dismutase 2 (SOD2), and glutathione (GSH) were determined using commercial kits.

Protein analyses (SIRT3, FoxO3a, NRF2, and NQO1), nuclear factor erythroid 2-related factor 2 (NRF2), NADPH oxidase 2 (NOX2) were performed by western blotting after lysis with radioimmunoprecipitation assay (RIPA) buffer, quantification by bicinchoninic acid (BCA) assay, separation via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and transfer to polyvinylidene difluoride (PVDF) membranes; blocking and Tris-buffered saline with Tween (TBST) procedures followed standard practice.

Stable SIRT3 knockdown was generated by lentiviral short hairpin RNA (shRNA) and verified by western blot. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) and Alizarin Red S staining. In vivo, male Sprague-Dawley rats received a high-fat/glucose diet, streptozotocin (STZ; 30 mg/kg), and intraperitoneal curcumin (10 or 50 mg/kg); bone microarchitecture was assessed by micro-computed tomography (μCT) and histology.

Study results

High glucose cut MC3T3-E1 viability, curcumin at 10 μM brought survival back toward normal; 1 μM and 100 μM had limited effect, so 10 μM was used for follow-ups. Apoptosis tracked with these changes: cleaved caspase-3 rose and B-cell lymphoma 2 (Bcl-2) fell under high glucose, and curcumin flipped both signals in a protective direction.

Electron microscopy showed swollen, cristae-disrupted mitochondria after high glucose, while curcumin treatment preserved a more normal morphology. JC-1 data echoed these findings: mitochondrial membrane potential dropped with high glucose but partially recovered after curcumin exposure.

Redox balance also improved. High glucose pushed ROS and MDA up and depressed endogenous defenses. Curcumin lowered ROS, reduced MDA, and boosted SOD2 and GSH toward control levels, evidence of a healthier oxidative state. At the signaling level, high glucose suppressed SIRT3, FoxO3a, NRF2, and NQO1, and NOX2; curcumin restored these proteins toward baseline, consistent with re-engaging mitochondrial deacetylation and antioxidant programs.

Knocking down SIRT3 removed the benefit. With SIRT3 silenced, curcumin no longer helped: viability fell, mitochondrial membrane potential dropped, and FoxO3a, NRF2, and NQO1 decreased compared with the high-glucose plus curcumin condition. This loss of protection identifies SIRT3 as the upstream driver connecting curcumin to antioxidant and cytoprotective effects.

Functionally, osteogenic differentiation followed suit. High glucose blunted maturation, but curcumin restored ALP staining, increased Alizarin Red S-positive nodules, and raised osteoprotegerin (OPG) and osteocalcin (OCN). Each gain was dampened by SIRT3 knockdown, tying the rescue to the SIRT3/FoxO3a axis and its downstream antioxidant signaling rather than nonspecific effects. In short, curcumin stabilized mitochondria, improved redox tone, reduced apoptosis, and allowed osteoblasts to proceed toward mineralization despite hyperglycemia.

The animal data matched the cell work. The STZ-plus-diet regimen produced hyperglycemia and modest weight loss, confirming a T2DM-like state. Untreated diabetic rats showed sparse, thin trabeculae and degraded architecture. Curcumin (10 or 50 mg/kg) improved μCT metrics, with denser trabecular networks and higher apparent bone density; HE sections looked healthier.

Immunohistochemistry showed higher SIRT3 and NRF2 in bone after curcumin, consistent with mitochondrial and antioxidant reactivation in vivo. These increases were dose-dependent, with higher curcumin producing greater protein expression changes. In a setting where standard therapies often lag, these cellular wins translated into tissue-level gains.

Conclusions

Curcumin protected osteoblasts and bone in diabetic-osteoporosis models by easing mitochondrial oxidative stress, preserving membrane potential, and promoting osteogenic differentiation. The effect required SIRT3 activation and FoxO3a signaling, coincided with stronger NRF2-dependent defenses (including NQO1), and disappeared with SIRT3 silencing.

In rats with a T2DM-like condition, curcumin improved trabecular microarchitecture on μCT and raised bone density indicators in parallel with increased SIRT3 and NRF2 expression in bone tissue.

These results highlight the SIRT3/FoxO3a axis as a therapeutic target, underscore its coordination with NRF2-driven antioxidant responses, and support curcumin as a practical, low-cost adjunct for diabetes-related bone fragility, meriting translational studies to refine dose, schedule, and long-term safety in humans.

The authors also position curcumin alongside other natural compounds like melatonin, groundnut extract, and geranium that target mitochondrial redox pathways, but note that its dual mitochondrial–epigenetic action may offer a broader protective profile.