This study compared the concentrations of trace elements in the plasma of OA patients and compared with healthy control. As expected, the concentrations of various trace elements in OA patients were found to be altered, including Zn, Mg, Fe, Mn, and Se, which were significantly lower than those in the control group, while plasma Ca levels were significantly higher. There was no significant difference in the levels of Cu and Pb in two groups. The concentrations of trace elements differed between male and female patients, with lower plasma levels of Mn and Se in female OA patients compared to healthy females of the same age, and lower levels of Zn and Mg in the plasma of male OA patients compared to healthy males of the same age, suggesting that the trace elements contributing to the development of OA may different with gender and should be treated differently. The results of correlation analysis indicated intricate associations between these trace elements, which will brings great difficulty to externally regulating of trace element content in the body. Logistic regression analysis suggested that gender and Se concentration were risk factors for the occurrence of OA. Correlation analysis found a positive correlation between Cu and oxidative stress, and a negative correlation between Zn and Se and oxidative stress, a negative correlation between Mn and the inflammatory cytokine IL-6, a positive correlation between Fe and IL-1β. This suggests that these trace elements may play a role in promoting or inhibiting inflammatory responses in the body, and changes in their concentrations may disrupt the oxidative and reductive balance in the body, further inducing the expression of inflammatory cytokines, leading to inflammation in the joints and damage to the cartilage.
Zn is a fundamental co-factor for enzymes involved in the synthesis of DNA, RNA, and proteins. It plays a crucial role in cellular membrane repair mechanisms and the regeneration of muscle and skeletal matrix. Zn has a dual role in bone: firstly, it plays a structural role in the bone matrix; secondly, it is involved in bone formation by stimulating osteoblasts and inhibiting osteoclasts, thus contributing to the preservation of bone mass. Studies have shown that low Zn concentrations can lead to osteogenic effects [9]. Zn not only acts as an inhibitor of bone tissue loss, but also plays an important role in cartilage metabolism, gene expression of type II collagen and SOX9, and production of matrix metalloproteinases (MMPs) which caused inflammation-related diseases. It has reported that Zn can prevent against monosodium iodoacetate induced cartilage degradation, which suggests that zinc has the potential to be a preventive supplement for OA [10]. This study found a significant decrease in Zn concentration in the plasma of OA patients, which is consistent with the findings of Wang et al [11]. This suggests that the decreased Zn concentration in patients with OA leads to a decrease in their antioxidant and anti-inflammatory capacity, and supplementation of Zn may provide a new therapeutic approach for inhibiting inflammation in OA patients. But on the other hand, excessive zinc can also generate redox stress and cause the destruction of articular cartilage [1, 12], so the detection in the supplement process is particularly important.
Mg is an important trace element in the human body and plays a crucial role in metabolic and energy balance. Despite that humans can obtain Mg from daily diet, inadequate Mg intake is not uncommon [13]. There are several possible reasons for Mg deficiency in older adults. Firstly, as age increases, intestinal absorption of Mg gradually decreases [14]. Secondly, Mg deficiency often occurs in chronic diseases [15], which are common in older adults. Although the conclusions are still controversial, more and more clinical studies have shown a close relationship between dietary Mg and osteoarthritis (OA) [16]. Until now, some studies have elucidated that Serum Mg concentration is inversely related to the severity of OA but not related with inflammation [17, 18]. Our research also found that Mg ion concentration in osteoarthritis patients was significantly lower than that in the healthy control group. As 99% of Mg locates in intracellular, the serum Mg is less than 1% of total Mg[16]. Therefore, further research is needed to explore new methods to assess Mg levels in the body and evaluate whether dietary or pharmacological Mg supplementation can improve or reverse osteoarthritis.
Fe is an essential trace element in many metabolic processes of chondrocytes, such as redox reactions, DNA synthesis, and cellular respiration [19, 20]. Maintaining normal cellular function requires precise regulation of Fe homeostasis, as excess Fe can damage cells by increasing the production of reactive oxygen species (ROS) [21]. However, the beneficial range of Fe concentration is narrow. Several independent clinical studies have found that individuals with high serum ferritin levels have a four-fold increased risk of developing OA, and serum ferritin levels are positively correlated with the severity of radiographic OA [22]. In this study, we found that Fe ion levels were lower in OA patients compared to health control, which is inconsistent with previous research [22]. The discrepancy may be due to different indicators being measured, as we measured free Fe ions while other studies measured bound Fe in the form of ferritin. Additionally, different detection methods were used, as we used mass spectrometry while other studies used ELISA or chemiluminescence assays.
Mn is a cofactor for various enzymes, including mitochondrial superoxide dismutase, phosphoglucomutase, and glycosyltransferase. Glycosyltransferase is involved in the synthesis of glycosaminoglycans, proteoglycans, and type II collagen in the extracellular matrix of chondrocytes [23]. The concentration of Mn in articular cartilage is relatively high, ranging from 1.37 to 2.21 µg/g, which is necessary for normal cartilage metabolism [24]. Mn can slow down the degeneration and promote the repair of articular cartilage. Das et al. [25] reported that the combination of Mn, glucosamine, and chondroitin sulfate can regulate the matrix metabolism of articular cartilage, alleviate symptoms of OA. The other research found that Mn deficiency can impair the biosynthesis of glycosaminoglycans, leading to cartilage dysplasia characterized by OA and deformities [26]. Mn has strong antioxidant capacity by scavenging oxygen free radicals, which can alleviate oxidative stress in articular cartilage caused by inflammation, reduce the severity of OA [27]. Additionally, Mn can enhance chondrocyte vitality and protect the extracellular matrix [27]. In this study, we found that the plasma concentration of Mn was lower in OA patients compared to the healthy population, and the Mn concentration was negatively correlated with the inflammatory factor IL-6. Therefore, supplement of Mn is a promising method for protecting cartilage from OA and reducing inflammation.
Se is an important component of selenoproteins and plays an essential role in antioxidant and anti-inflammatory processes [28]. Studies have shown that low Se levels may be associated with a higher risk of developing radiographic OA [29]. A cross-sectional study involving 1032 participants with radiographic OA found that individuals with lower plasma Se levels had a higher risk of developing radiographic OA, and this relationship showed a dose-response pattern [11]. In vitro studies have demonstrated that Se can neutralize the inflammatory response induced by interleukin-1β (IL-1β) in chondrocytes [30]. Our study also found that the Se concentration in OA patients was significantly lower than the healthy people, and it was identified as a protective factor for OA. Revealing these potential connections is beneficial for researchers to develop new preventive and therapeutic approaches for OA.
Ca is an essential nutrient in the human body and plays a key role in regulating various physiological processes. In healthy individuals, serum Ca levels are regulated by internal balance mechanisms such as Ca-sensitive receptors, 1,25-dihydroxyvitamin D, and parathyroid hormone. Two studies have indicated a negative correlation between serum Ca levels and OA [31, 32]. However, these studies did not find a connection between OA and blood Ca concentration [33–35], the reason why these studies have different conclusions is that they were conducted on Western populations whose lifestyles and dietary habits were different from those of Asians. Our study found that the plasma Ca ion concentration in OA patients was higher than in the healthy population, but we did not assess the bone metabolism of these patients or investigate whether they had accompanying osteoporosis.
Cu is essential for normal growth, development, and skeletal health in the human body, which has an important influence in the internal balance of cells and body fluids, and involves in immune cell function and maintains stable body defense. A recent study illustrated that Cu can promote the regeneration of articular cartilage and subchondral bone by activating the immune response of cartilage, which is beneficial for the reconstruction of the cartilage-bone interface and the recovery of cartilage lesions [36]. So, Cu deficiency can reduce bone strength, impair cartilage integrity, and increase the incidence of OA [36, 37]. It has been reported that dietary supplementation of Cu can reduce the severity of cartilage diseases and other developmental cartilage lesions, possibly due to improved collagen cross-linking, enhanced synthesis of type II collagen and antioxidant capacity [38, 39]. However, the effect of Cu on OA may be bidirectional, because Cu has both pro-oxidative and anti-oxidant properties. As the concentration of free Cu increases, the oxidative ability of Cu exceeds its own antioxidant capacity, the over-excess Cu could lead to joint damage [40]. The plasma Cu concentration in some OA patients this study included were significantly higher than that of the healthy control, but there was no significant difference overall between two groups, possibly because some patients who had used anti-inflammatory drugs were not completely excluded from case group.