Study on the mechanism of curcumin in protecting osteoblast function through antioxidant stress
Osteoporosis is one of the most common degenerative diseases of bone, characterized by low bone mass, changes in bone microstructure, and increased risk of fractures, which seriously affect the lives of elderly people, especially postmenopausal women. Osteoblasts are responsible for bone formation, while osteoclasts participate in bone resorption. The pathological and physiological basis of osteoporosis is an increase in osteoclast absorption, while osteoblast dysfunction leads to reduced bone formation and net bone loss. Research has shown that oxidative stress is a key pathogenic factor in osteoporosis, and the dysfunction of osteoblasts caused by excessive oxidation leading to osteogenesis deficiency is an important cause of net bone loss in the development of osteoporosis. Oxidative stress not only inhibits osteoblast differentiation and proliferation, but also induces cell death. Therefore, reducing oxidative stress through drug intervention can help protect the function of osteoblasts and reduce their death, which has a certain effect on improving osteoporosis.
Curcumin (Cur) is a yellow substance found in the rhizome of turmeric, which has anti-inflammatory, antioxidant, antibacterial, and anticancer effects. It is often used as a spice and potent herb. According to Li et al., Cur pretreatment reduces osteoblast apoptosis and maintains its differentiation function by eliminating the inhibitory effect of reactive oxygen species (ROS) on the GSK3 β – Nrf2 signaling pathway. In addition, the liposome Cur released by the 3D printed scaffold has significant cytotoxicity against osteosarcoma (bone cancer) cells in vitro, but promotes the survival and proliferation of osteoblasts (healthy bone cells). However, the effect of Cur on osteoblast proliferation under oxidative stress and its regulatory mechanism on osteoblast redox system are currently unclear. Therefore, this study used hydrogen peroxide (H2O2) to induce oxidative stress and construct a functional impairment model of osteoblasts. By observing the regulatory effects of Cur on cell activity, proliferation, differentiation, and the redox system, the mechanism by which Cur protects the function of osteoblasts under oxidative stress was elucidated.

Oxidative stress injury is one of the main pathologies of osteoporosis and/or osteonecrosis, and adding H2O2 to culture medium to induce osteoblast dysfunction is an established cell model that simulates osteoporosis. H2O2 is a common reactive oxygen species (ROS) with a long half-life and easy penetration of various plasma membranes, which can induce significant lipid oxidation, protein damage, and DNA fragmentation, ultimately leading to cell death and functional impairment. In this study, H2O2 was used to treat primary osteoblasts in rats, resulting in a decrease in cell activity, proliferation rate, and differentiation rate, accompanied by an imbalance of oxidation-reduction, indicating the successful construction of an osteoblast oxidative stress injury model.
At present, the drugs used to treat osteoporosis mainly include bisphosphonates, hormone therapy, selective estrogen receptor modulators, calcitonin, denosumab, calcium and vitamin D supplements. Recently, synthetic metabolic drugs such as teriparatide, strontium ranelate, and Romuximab have been launched on the market. A network meta-analysis study showed that different drugs have different therapeutic effects on osteoporosis in different parts of the body. In addition, the safety issues and adverse side effects of some drugs also need to be taken seriously. Therefore, researchers are screening the efficacy of natural medicines in order to find effective and low side effect treatments for osteoporosis. At present, research has found that natural antioxidants such as Cur, resveratrol, camellia, etc. can provide safer and more effective alternative treatment strategies. However, the mechanism by which Cur improves osteoporosis is not fully understood. Therefore, this study aims to explore the mechanism by which Cur protects osteoblasts against oxidative stress damage from the perspectives of redox and signaling pathways. Our experimental data shows that Cur at various concentrations can inhibit H2O2 mediated excessive oxidation and promote osteoblast proliferation under stress, indicating a wide range of safe and effective concentrations for its pharmacological effects.
The antioxidant capacity of cellular tissues depends on the clearance of ROS by their endogenous antioxidant system. However, in pathological conditions, the weakened clearance capacity of cellular tissues leads to oxidative damage to cellular components and functional impairment. In the osteoblast oxidative damage model, a decrease in T-AOC and SOD levels indicates a weakening of the cell’s antioxidant capacity, while an increase in MDA levels suggests excessive oxidation of the cell’s lipid components. After intervention with gradient concentration of Cur, there was an improvement in redox imbalance. These findings suggest that Cur may directly neutralize ROS through its own reducing groups, and indirectly clear ROS by upregulating the activity of endogenous antioxidant enzymes such as SOD. Oxidative stress also causes tissue and cell damage by activating p38 MAPK, and the phosphorylation level of p38 MAPK represents its activation state. Western blotting results showed that different concentrations of Cur could inhibit H2O2 mediated phosphorylation of p38 MAPK, suggesting that the inhibitory effect of Cur on p38 MAPK activation may be involved in its protective mechanism against oxidative damage in osteoblasts. However, due to the imbalance of endogenous antioxidant systems of different types, the types of ROS produced vary, resulting in different effects on cell survival, death, and function. We will further explore the redox regulatory mechanisms of osteoporosis in future research.
This study also found that Cur can improve the inhibition of H2O2 on osteoblast differentiation function, manifested by an increase in mineralized calcium nodules and elevated ALP activity, which is consistent with the research reported by Li et al. The enhanced osteogenic differentiation ability after Cur pretreatment may be related to increased cell proliferation and ALP activity. However, Cur at a concentration of 10 μ oml/L did not show significant promotion of bone differentiation, suggesting that maintaining good cell activity and proliferation ability may be more beneficial for the differentiation function of osteoblasts. In addition, ROS, as a signaling molecule, also plays its physiological functions, and excessive antioxidant activity may actually be detrimental to the normal function of cells. Although pre-treatment with 10 μ oml/L Cur can effectively inhibit lipid peroxidation, its protective effect on the endogenous antioxidant system is not as significant as low concentration Cur. Therefore, when Cur is applied at the animal and human levels, the appropriate dosage should be controlled. The Wnt signaling pathway has been confirmed to play a positive regulatory role in the process of osteogenic differentiation. Excessive ROS can promote the transcription of key genes in the Wnt/β – catenin pathway to be regulated by FoxO, ultimately inhibiting osteoblast proliferation, differentiation, and mineralization, leading to osteoporosis. We further explored the possible mechanism by which Cur protects the differentiation function of osteoblasts through Western blotting, and found that Cur can reverse the downregulation of Wnt5a and β – catenin expression mediated by H2O2, indicating that Cur may promote the proliferation, differentiation, and mineralization of osteoblasts under oxidative stress by regulating the Wnt/β – catenin signaling pathway.
In summary, this study used a gradient concentration of Cur to pretreat rat osteoblasts, observed its improvement effect on oxidative stress-induced osteoblast dysfunction, and preliminarily elucidated its mechanism of action. In the future, further basic and clinical research on the application of natural compounds such as Cur is needed to provide theoretical basis for the development of safe and effective anti osteoporosis treatment strategies. In addition, the dosage, administration method, drug metabolism, and efficacy evaluation of Cur are also scientific issues worth exploring.