Osteoporosis is a chronic metabolic disease, mainly related to estrogen deficiency in the postmenopausal body. Domestic and international studies have confirmed that oxidative stress plays an important role in the pathogenesis of osteoporosis, and that reactive oxygen species generated by oxidative stress have an effect on the activity and function of both osteoblasts and osteoclasts in the body; lycopene is a strong antioxidant that exists in nature and is widely found in fresh fruits and vegetables, and previous epidemiological surveys, clinical studies and in vitro cell cultures have confirmed that lycopene has a preventive effect on human Since oxidative stress plays an important role in the pathogenesis of osteoporosis, and lycopene has antioxidant function, scholars at home and abroad predict that lycopene consumption can prevent the occurrence of osteoporosis, and many basic and clinical studies have been conducted on this. In this paper, we review the current research on lycopene in osteoporosis at home and abroad.
Overview of osteoporosis
Throughout life, bone tissue is in a continuous process of reconstruction, which includes the lysis of old bone tissue by osteoclasts and the formation of new bone tissue by osteoblasts [1, 2], and a variety of cytokines are involved and play an important role in this complex process under the regulation of genes. These factors include interleukins, transforming growth factor, tumor necrosis factor, colony-stimulating factor, etc. These factors affect the differentiation, proliferation, maturation and activation of osteoblasts and osteoclasts through autocrine and paracrine actions, regulating the balance between bone resorption and bone reconstruction, and osteoporosis occurs when this balance is disrupted, resulting in increased osteoclast gene expression and insufficient osteoblast gene expression [3]. Osteoporosis is still primarily a metabolic disease, which is essentially characterized by a decrease in bone mass in bone tissue and a degradation of the microstructure of bone, with a consequent increase in bone fragility and a high susceptibility to fracture [5]. Postmenopausal osteoporosis is the most common primary osteoporosis and is caused by a decrease in estrogen in the body and an increase in the activity of osteoclasts, resulting in bone loss. However, the mechanism of how estrogen deficiency increases osteoclast activity is not well understood [6]. Some reports have confirmed that intracellular reactive oxygen species (ROS) can significantly increase osteoclast activity and lead to osteoporosis [7], and Jenny M.L et al [8] pointed out through their study that estrogen deficiency leads to a decrease in the concentration of thiol antioxidants in osteoclasts, which increases the sensitivity of osteoclasts to osteoclast gene signaling, and it makes ROS-mediated overproduction of cytokines (e.g. IL-1, TGF-a), all of which increase osteoclast activity and ultimately lead to the development of osteoporosis.
Oxidative stress and antioxidants
Oxidative stress in the human body is the result of a weakened defense system or excessive production of reactive oxygen species (ROS), which are oxygen-containing free radicals produced by aerobic metabolism in living organisms and consist mainly of superoxide anion (O2-), hydroxyl radical (-OH) and hydrogen peroxide (H2O2 ) [9]. Under normal physiological conditions, reactive oxygen species are continuously produced and scavenged by antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH2px) and some low molecular weight antioxidants [10]. When this balance is disrupted by aging, cancer, and estrogen deficiency, the oxidative stress caused by the abnormal increase of ROS causes a series of oxidative damage to the biological organism, such as attacking polyunsaturated fatty acids causing lipid peroxidation and altering the structure and function of biological membranes and cell membrane surface receptors; damaging the sulfhydryl and amino groups of proteins causing protein denaturation, cross-linking, and loss of enzyme activity; damaging DNA leading to DNA strand breaks and mutations; meanwhile, oxidative stress accelerates cellular senescence and death by affecting many cytokines such as nuclear factor (NF-κB), mitogen-activated protein kinases (MAPKs), P53, and heat shock factor (HSF) [11, 12].
Oxidative stress, antioxidants and osteoporosis
Reactive oxygen species generated by oxidative stress play an important role in the pathogenesis of osteoporosis. Epidemiological studies [13,14,15] have shown that certain antioxidants such as vitamins C, E and β-carotene may reduce the occurrence of osteoporosis and decrease the risk of fracture in women with osteoporosis. Antioxidants were significantly lower in the serum of women with osteoporosis [16], and reactive oxygen species were increased and antioxidant enzymes such as superoxide dismutase (SOD) were decreased in ovariectomized rats [17]. In a study of postmenopausal osteoporosis model rats, Isomura H et al. indicated that oxidative stress is involved in the pathological process of metabolic bone diseases such as osteoporosis, as evidenced by decreased alkaline phosphatase activity and reduced salmon calcitonin levels in the blood of model rats [18], while in recent years, through a controlled study of oxidative stress status in 22 osteoporotic patients compared to normal women of the same age group Yousefzadeh G et al [19] further confirmed that osteoporotic patients are in a high oxidative stress state and that moderate doses of antioxidants are beneficial for osteoporotic patients. In a study on the relationship between bone mineral density and oxygen radicals and antioxidants in men with osteoporosis, Yalin S [20] found that SOD levels in osteoporotic patients were negatively correlated with bone mineral density, suggesting that oxidative stress also plays an important role in the pathogenesis of osteoporosis in men. To further reveal the relationship between osteoporosis and oxidative stress and antioxidants, Ozqocmen S [21] et al. conducted a controlled clinical trial on the relationship between intraerythrocytic antioxidants and bone mineral density and the indices related to redox reactions in vivo after taking drugs for the treatment of osteoporosis, which showed that hydrogen peroxide and glutathione peroxidase activities were significantly reduced in women with osteoporosis, while lipid peroxidation This suggests that the development of osteoporosis is associated with an increase in oxidative stress and a decrease in antioxidants in the body, and that pharmacological treatment of osteoporosis works by reducing the redox response in the body and strengthening the function of the antioxidant system in the body. Although the above studies have confirmed the correlation between oxidative stress and osteoporosis, the detailed mechanisms of action of oxidative stress and osteoporosis at the cellular and molecular levels are not well understood.
Oxidative stress, antioxidants and osteoclasts
Regarding the differentiation and proliferation of osteoclasts and their ability to promote bone resorption are regulated by many factors; some researchers [22] demonstrated that reactive oxygen species play an important role in this process and that reactive oxygen species such as hydrogen peroxide and superoxide anion stimulate osteoclast inner core factor through the extracellular signal-regulated kinases (ERKs) and the cAMP response element binding protein of egg kinase (PKA-CREB) pathway Kim H et al [23] investigated the relationship between redox state in vivo and osteoclast and bone resorption, they analyzed glutathione synthase, glutathione synthesis rate-limiting enzyme and total glutathione and sulfhydryl content in vivo, and found that along with osteoclastogenesis and bone resorption It was found that the oxidative stress status in vivo was elevated along with enhanced osteoclastogenesis and bone resorption. And when the level of oxidative stress is elevated to a certain extent, it keeps osteoclastogenesis and inhibits bone resorption. Vaaraniemi J et al [24] found that osteoclasts promote bone matrix resorption at the cellular level by secreting acid and lysozyme into the resorption lumen between the cell membrane and the bone surface. The osteoclasts promote bone resorption by secreting acids and lysosomal enzymes such as histone K into the lumen between the cell membrane and the bone surface. This bone resorption-promoting function is achieved through the secretion of reactive oxygen species by the osteoclast anti-tartrate acid phosphatase (TRACP) in the cytosolic vesicles causing degradation of collagen and other proteins.
The antioxidants are also closely related to the osteoclast function, Nakagawa H [25] et al. found that EGCGS induced osteoclast death mainly through the hydroxyl group in its molecular structure by studying the mechanism of action of the antioxidant epigallocatechin gallate (EGCG) to induce osteoclast death. Lean J et al [26] found that the expression of the antioxidant thioredoxin-1 Trx was significantly increased in osteoblasts, and they transfected RAW264.7 cells with the Trx expression plasmid and found that osteoblast proliferation was significantly enhanced. After transfecting the cells with the antioxidant glutathione peroxidase-1 (Gpx), they found that Trx expression and osteoclast proliferation were inhibited again, and through further studies, they indicated that the oxidant promoted osteoclast proliferation by stimulating Trx expression in osteoclasts, resulting in increased expression of intracellular cytokines that promote cell proliferation. The addition of antioxidants such as glutathione peroxide can prevent the expression of Trx and thus prevent the proliferation of osteoclasts. Many foreign scholars have also demonstrated that the addition of antioxidants such as catalase [27], estrogen [28], homocysteine [29] and other antioxidants to the cell culture medium can also reduce the production of intracellular reactive oxygen species through in vitro osteoclast culture. It has been inferred that antioxidants in nature may also have the function of counteracting the production of reactive oxygen species in osteoclasts and thus inhibiting osteoclastic bone resorption.
Oxidative stress and antioxidants and osteoblasts
Oxidative stress can inhibit osteoblast differentiation and induce osteoblast death.Arai M [30] et al. studied the effect of oxidative stress on osteoblast mineralization.They added the oxidant H2O2 to the medium of osteoblast MC3T3-E1 cells; they found that the mineralization level of MC3T3-E1 cells was reduced by half and also found that the transcription factor Nrf2, which regulates antioxidant enzymes They also found that the gene expression of Nrf2, a transcription factor that regulates antioxidant enzymes, was increased. In addition, they found that the gene expression of the bone-derived markers Runx2, ALP, and BSP was significantly lower than in the group of cells not treated with H2O2. This suggests that oxidative stress inhibits the mineralization function of osteoblasts by upregulating the regulatory genes of antioxidant enzymes. By adding the antioxidant turmeric (curcumin) to the culture medium of osteoblasts, Chan WH et al [31] from Taiwan, China, also found that antioxidants could affect the production of reactive oxygen species and intracellular ATP levels in osteoblasts ultimately leading to nuclear cleavage and cell death.Samoto H [32] et al. investigated the effect of oxidative stress on osteoblasts at the molecular level. They treated osteosarcoma cells ROS17/2.8 with tumor necrosis factor а (TNF-а) (10 ng/ml) and found that intracellular mRNA of bone salivary protein (BSP), which plays an important role in bone mineralization, was significantly reduced after 24 h. Pretreatment with the antioxidant N-acetyl-cysteine (20 Mm), followed by the addition of TNFu-а after 30 min was mRNA content of intracellular BSP was not significantly reduced, thus suggesting that many substances affect osteoblast function through intracellular oxidative stress.Nam SH [33] et al. found that H2O2 regulates intracellular Ca2+ activity in osteoblasts by increasing the release of Ca2+ from the intracellular Ca2+ pool, ultimately leading to osteoblast death.Vali B [34] et al. investigated the effect of the antioxidant epigallocatechin gallate (EGCG) on osteoblasts found that it prevents the production of reactive oxygen species in osteoblasts and stimulates osteoblast differentiation and promotes the formation of mineralized nodules. It is evident from the above that oxidative stress and antioxidants affect the proliferation and differentiation of osteoblasts through multiple pathways, ultimately influencing the formation and mineralization of the strands.
Lycopene and oxidative stress
Lycopene is an effective antioxidant present in nature and cannot be synthesized in the human body. Lycopene in the diet is mainly obtained from fresh vegetables and fruits, with tomatoes containing the most, followed by watermelon and purple grapes. Heat-treated tomatoes are more favorable for lycopene absorption than untreated tomatoes, as the heated lycopene is converted from its original all-trans structure to the cis-isomer [35]. The average daily intake of lycopene from food varies among people in different countries and regions, with an average of 8.2 mg/day. One study showed that the daily intake of 7 mg of lycopene from heat for 14 days reduced oxidative damage to DNA in peripheral blood lymphocytes [36]. The results of another study showed that the daily intake of 30 mg to 75 mg of lycopene was safe and beneficial without side effects, and that higher than 75 mg/day did not significantly affect the blood levels of lycopene [37].
Lycopene is a carotenoid because its chemical structure contains 13 double bonds, 11 of which are conjugated, which determines its strong antioxidant properties, and lycopene is twice as reducing as β-carotene and 10 times more reducing than vitamin E [38]. This powerful reducing function allows it to play an important role in the prevention of chronic human diseases. From initial epidemiological investigations showing that lycopene consumption reduced the incidence of prostate cancer [36], later researchers gradually found through epidemiological investigations and in vitro intervention trials that lycopene consumption not only prevented cancer, but also coronary heart disease, hypertension, diabetes, metaplasia, female infertility and neurodegenerative diseases [39]. All these effects are related to the antioxidant function of lycopene itself, including the protection of protoplasmic lipoproteins, lymphocyte DNA, and serum proteins from oxidative damage [40]. Based on this principle of lycopene’s antioxidant properties, researchers have found that it also has an important role in the prevention and treatment of osteoporosis.
Lycopene and osteoclasts
Studies related to lycopene and osteoclasts have been reported relatively rarely, RAO et al [41] investigators extracted osteoclasts from rat femoral bone marrow for culture and then added different concentrations of lycopene and thyroid hormone together or separately to the culture medium, and after observing the changes in the amount of antitartaric acid phosphatase (TRACP) and oxidative metabolite methanothione in the culture medium, it was found that regardless of Lycopene inhibited bone resorption in osteoclasts regardless of the presence or absence of parathyroid hormone, and this inhibition was associated with the inhibition of the TRACP oxidase system in osteoclasts and thus the synthesis and secretion of intracellular ROS. We incubated osteoblasts with different concentrations of lycopene and found that different concentrations of lycopene (10-7 to 10-5) had an effect on osteoblasts (article to be published).
Lycopene and osteoblasts
Kim et al [42] were the first to add lycopene to the medium of osteoblast SaOS-2, and the number of SaOS-2 cells in the medium increased with time, from which they concluded that lycopene stimulates the proliferation of osteoblast SaOS-2 cells in a time-dependent manner, and their results showed that lycopene has a beneficial effect on the proliferation of more mature osteoblast alkaline phosphatase ( ) activity in more mature osteoblasts, but not in young osteoblasts. Our study also confirmed that lycopene at different concentrations of lycopene promoted osteoblast proliferation, alkaline phosphatase expression and bone mineralization. The exact mechanism of action of lycopene on osteoblasts at the molecular level is not well understood and more in-depth studies are needed.
Lycopene and postmenopausal osteoporosis
Clinical studies related to lycopene and osteoporosis have been reported relatively rarely, and epidemiological data show that the consumption of fresh fruits and vegetables rich in lycopene significantly reduces the risk of osteoporosis [44]. Recently .Rao L.G [45] et al. conducted a 7-day clinical trial of lycopene containing foods in 13 postmenopausal women aged 50-60 years and finally examined the correlation between fasting serum lycopene levels, lipid peroxidation reaction, protein sulfhydryl content, I-collagen cross-linked amino-terminal peptide (NTX, bone resorption) and bone alkaline phosphatase (bone formation) and showed that With the increase of lycopene in serum, protein oxidation (protein sulfhydryl groups) was significantly reduced, along with a significant decrease of NTX content in blood. This suggests that lycopene can reduce oxidative stress in the body, which may prevent the development of osteoporosis.
In summary, lycopene affects the function of osteoblasts and osteoclasts through its antioxidant function, which can effectively intervene in the pathological process of osteoporosis development and ultimately prevent and slow down the onset of osteoporosis. However, there is not much evidence on this aspect of research, such as the direct mechanism of action of lycopene’s antioxidant function is not well understood, and there is a lack of effective animal studies and clinical studies on the effects of lycopene on osteoporosis in large samples. We are currently conducting animal studies on lycopene and osteoporosis and hope that in the near future dietary lycopene therapy can be used instead of drugs to treat osteoporosis or become an effective adjunct to drug therapy for osteoporosis.