Front. Endocrinol. Frontiers in Endocrinology Front. Endocrinol. 1664-2392 Frontiers Media S.A. 10.3389/fendo.2025.1634580 Review RETRACTED: From molecular mechanism to plant intervention: the bidirectional regulation of inflammation and oxidative stress in bone aging LiQi 1 Writing – original draft Conceptualization ZhaoXiumei 2 Writing – original draft WangAnning 3 Formal analysis Writing – original draft HangTingting 3 Writing – original draft Software ZhaoJianpeng 3 Writing – original draft Software ZhangShengkai 3 Writing – original draft Data curation ZengLingfeng 4 * Writing – review & editing WangWeiguo 1 3 * Funding acquisition Conceptualization Writing – review & editing Resources Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong, Jinan, China Second Department of Clinical Psychology, Shandong Mental Health Center, Shandong, Jinan, China First School of Clinical Medicine, Shandong Traditional Chinese Medicine University, Shandong, Jinan, China Department of Orthopedics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China Correspondence: Lingfeng Zeng, zenglf6768@163.com; Weiguo Wang, 60170005@sdutcm.edu.cn 09 07 2025 29 01 2026 2025 16 1634580 24 05 2025 13 06 2025 Copyright © 2025 Li, Zhao, Wang, Hang, Zhao, Zhang, Zeng and Wang. 2025 Li, Zhao, Wang, Hang, Zhao, Zhang, Zeng and Wang https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

This article systematically elaborates the central role of inflammatory response and oxidative stress in osteoporosis (OP) and cartilage injury, and reveals the molecular mechanism by which the two damage bone homeostasis through NF-κB, RANKL and other signaling pathways. Studies have shown that plant natural products (such as hesperidin, curcumin, Epimedin B, etc.) can improve bone metabolism imbalance and delay the process of bone aging by regulating inflammatory factors (TNF-α, IL-1β) and antioxidant pathways (Nrf2/HO-1). Osteoporosis and cartilage damage promote each other to form a vicious cycle, and the intervention of plant active ingredients can target this common pathological process. Based on the current evidence, the strategy of combining anti-inflammation, anti-oxidation and mechanical regulation may provide a new direction for the prevention and treatment of bone aging-related diseases.

 osteoporosis bone aging cartilage injury inflammatory response oxidative stress signaling pathways plant-based natural products Health Commission of Shandong Province 10.13039/501100020206 M20241721 The author(s) declare that financial support was received for the research and/or publication of this article. Application and effect evaluation of total Eucommia capsule in postoperative rehabilitation of patients with fragile fracture of spleen and kidney Yang deficiency, China Association of Traditional Chinese Medicine;GB_CACM_2024005, Clinical application and mechanism of Zhuanggu Shenjin pill in the treatment of perimenopausal osteoporosis and Health Commission of Shandong Province; M20241721. section-at-acceptance Bone Research Introduction

With the increasing aging of the population, the impact of osteoporosis on people’s health has become more serious (1). Osteoporosis can lead to a variety of diseases. For the elderly, joint pain is one of the factors that disturb the daily life of patients. Joint pain caused by osteoporosis will not only affect the mobility of the elderly, but also have a negative impact on their psychological state (2). Many elderly people are reluctant to go out because of joint pain, and their social circle is gradually shrinking, resulting in loneliness and depression (3). The main cause of joint pain is cartilage damage. As an important part of the joint, cartilage injury can lead to increased friction on the articular surface, which in turn causes pain and inflammation (4). When osteoporosis occurs, the density and quality of bone decrease, which weakens the support effect of bone on joints, further increases the burden of cartilage and accelerates the damage process of cartilage. Recent studies highlight the potential of plant-based interventions (e.g., flavonoids, polyphenols) to modulate inflammatory and oxidative pathways, offering novel therapeutic avenues for bone aging. This article mainly discusses the relationship between the pathogenesis of osteoporosis and cartilage damage and the research of related traditional Chinese medicine treatment, in order to provide theoretical support for the next experimental research and clinical application.

 The research into the pathogenesis of osteoporosis and cartilage damage

OP is a systemic disease caused by the loss of bone mass, resulting in the decrease of the number of bone trabeculae in bone tissue and the increase of bone fragility. There are various reasons leading to bone mass loss, which are currently believed to be mainly inflammatory response, oxidative stress response, hormone imbalance, malnutrition and lack of exercise (5–7). Cartilage injury is generally a state of hyaline cartilage damage on the surface of the finger joint, the most important of which is traumatic cartilage injury, in addition to inflammatory response, oxidative stress response, aging and genetic factors (8–11). Among them, inflammatory response and oxidative stress play a major role in the pathogenesis of OP and cartilage damage without external force influence (Figure 1).

Correlation between osteoporosis and the pathogenesis of cartilage damage.

Venn diagram illustrating factors of osteoporosis and cartilage injury. The left blue circle shows osteoporosis factors: hormonal imbalance, malnutrition, lack of exercise. The right red circle indicates cartilage injury factors: increase in age, genetic factors. The overlapping purple area lists common factors: inflammatory response, oxidative stress response. The relationship between inflammatory response and cartilage damage in osteoporosis The role of inflammatory response in osteoporosis and its related pathways Role of inflammatory response in osteoporosis

Osteoporosis is a common bone disease, its pathogenesis is complex, and inflammatory response plays a crucial role in the pathogenesis of osteoporosis. A large number of studies have shown that inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β, IL-6, IL-10, IL-12p70, IL-17, IL-18, and IL-23, have significant effects on nuclear factor-κB ligand (RANKL), Cathepsin K (CTSK) and nuclear factor-activated T cell 1 (NFATc1) are associated with increased risk of osteoporosis (12–14). Studies have shown that inflammatory factors may increase bone turnover and destroy the coupling between osteoblasts and osteoclasts, eventually leading to bone loss, thus accelerating osteoporosis (15). These inflammatory factors not only affect bone metabolism through inflammatory response, but also affect osteoblasts through apoptosis, pyroptosis and autophagy, leading to osteopenia and bone structure destruction (16–18). A large number of studies have found that inhibiting the secretion of inflammatory factors has an important effect on the treatment of osteoporosis (Table 1).

Inflammatory factors associated with osteoporosis and cartilage damage.

Osteoporosis-related inflammatory factors Inflammatory factors related to cartilage injury
Name Mechanism of action Name Mechanism of action
TNF-α RANKL expression was stimulated to promote osteoclast differentiation;Inhibition of osteoblast activity (Wnt/β-catenin pathway inhibition) TNF-α Up-regulation of ADAMTS-5 (aggrecanase);It promoted the apoptosis of chondrocytes;It acts in concert with IL-1β to enhance inflammation
IL-1β Synergistic enhancement of RANKL signaling;The COX-2/PGE2 pathway is induced to promote bone resorption IL-1β Activation of MMPs;Inhibition of collagen II and proteoglycan synthesis;Induction of NO production (via iNOS)
IL-6 It promoted osteoclastogenesis through the gp130/JAK/STAT3 pathway;Levels are increased in postmenopausal women with estrogen deficiency IL-6 Activation of STAT3 pathway promoted the expression of MMP-3/13;The formation of synovial pannus was induced
IL-17 Direct stimulation of RANKL secretion;Promotes inflammatory bone destruction IL-17 The release of MMP-9 from chondrocytes was stimulated;Promotes RANKL-mediated subchondral bone erosion
M-CSF It cooperates with RANKL to support osteoclast precursor survival and differentiation IL-18 Enhanced NF-κB signaling and amplified the effect of IL-1β;Promote chemokine release
IL-7 Inhibition of Wnt signaling pathway and reduction of osteoblast differentiation IL-4/IL-13 Inhibits MMPs but simultaneously reduces collagen synthesis (dual effect);Promoting fibrosis repair
IL-15 It also reduced Runx2 expression and inhibited bone formation TGF-β Profibrotic (promotes replacement of type I collagen for type II collagen);Osteophyte formation was induced at high concentrations
Related pathways of inflammatory response in osteoporosis

In recent years, studies on signaling pathway mechanisms have found that there are some classic inflammation-related pathways such as NF-κB pathway, RANKL/NF-κB pathway, and AMPK/mTOR pathway (19–22).

NF-κB

Recent studies have shown that Epimedin B (EB) can play an anti-inflammatory role by regulating the MAPK/NF-κB/NOD signaling pathway, and EB has been shown to have the effect of treating osteoporosis (23). It has also been found that nuclear receptor 77 (Nur77) can inhibit osteoclast differentiation by inhibiting the NF-κB signaling pathway, which proves that the NF-κB signaling pathway is of great significance in the prevention and treatment of osteoporosis (22) (Figure 2).

Pathway map of inflammatory response related to osteoporosis and cartilage injury (NF-κB regulated the transcription of pro-inflammatory factors (TNF-α, IL-1β, IL-6); When activated, it promotes osteoclast differentiation and inhibits osteoblast activity. RANKL/RANK: RANKL binds RANK receptors and recruits TRAF6 to activate the NF-κB/MAPK cascade, inducing the expression of NFATc1, driving osteoclast formation and bone resorption. MAPK/NF-κB mediates IL-1β-induced inflammatory response; Phosphorylation of p38 promotes the nuclear translocation of p65, upregulates the expression of MMP3/MMP13/ADAMTS5, and accelerates the degradation of cartilage matrix. AMPK/mTOR: energy stress response pathway; High-fat diet activates mTORC1 by inhibiting AMPK phosphorylation, promotes adipogenesis and inhibits Runx2 osteogenic transcription. AKT/mTOR: activation can promote autophagy of chondrocytes and maintain cartilage homeostasis; Inhibition of PI3K/Akt can block the release of inflammatory factors.) (Created with BioGDP.com).

Diagram of signaling pathways involved in inflammation and cell proliferation. It shows various proteins and molecules like IL-1β, TNF-α, RANKL, and IGF1/INS activating different cascades. Key proteins include MyD88, AMPK, and mTOR, leading to effects on NF-kB, ERK, and other transcription regulators. Arrows indicate activation, inhibition, and regulation of transcription processes related to cellular responses such as proliferation, inflammation, and anti-apoptosis. RANKL/RANK

The investigators found that RANKL, which binds to the RANK receptor, activates estnf receptor-associated factor 6 (TRAF6) and induces inhibition of the expression of nuclear factor of activated T cells 1 (NFATc1), thereby inhibiting the expression of proteins involved in osteoclastogenesis and bone resorption (24). In addition, it has been found that RANKL/NF-κB axis is the core switch of bone resorption. RANKL binds to RANK, an osteoclast precursor cell receptor, and recruits TRAF6 to activate NF-κB and MAPK cascades (25) (Figure 2).

 AMPK/mTOR

Some researchers have found that MPK/mTOR pathway regulates bone remodeling in response to energy stress. High-fat diet activates mTORC1 by inhibiting AMPK phosphorylation, resulting in PPARγ overexpression to promote adipocyte differentiation while inhibiting Runx2 osteogenic transcription (26). With the continuous improvement of people’s material life, high-fat diet obesity will lead to chronic low-grade systemic inflammation. Studies have found that folic acid can effectively prevent the occurrence of osteoporosis induced by high-fat diet through AMPK pathway (27) (Figure 2).

Moreover, in addition to the main pathways mentioned above, hesperidin has been found to promote osteoblast-mediated bone formation and inhibit proinflammatory cytokines through the estrogen signaling pathway. In summary, through the further study of inflammation-related pathways, the pathogenesis and treatment of osteoporosis have been further understanding and breakthrough, providing important theoretical basis and new ideas for the pathogenesis and treatment of osteoporosis, and bringing more hope to patients with osteoporosis.

 The role of inflammatory response in cartilage injury and its related pathways Role of inflammatory response in cartilage injury

Cartilage injury is a common clinical problem, and its pathogenesis is complex and involves many factors. Among them, the inflammatory response plays a crucial role in the occurrence and development of cartilage injury. Although the inflammatory response is a natural defense mechanism of the body against injury or infection, it can get out of control in the case of cartilage damage, leading to further destruction of cartilage tissue. Among them, the most important influencing factors are IL-1β, IL-3, IL-6, IL-8, TNF-α, Toll-like receptor (TLR) -8, matrix metalloproteinase (MMP) -13, prostaglandin E receptor 3 (PTGER3), (28–31). Through in-depth research on related inflammatory markers, It can regulate the inflammatory microenvironment of joints in multiple dimensions to make it more conducive to cartilage regeneration (8). In addition, some researchers have successfully engineered cartilage that can promote integration with native cartilage even under pro-inflammatory conditions through genetic technology, which provides a new treatment idea for cartilage injury (32). By inhibiting the inflammatory response, it can promote cartilage repair, reduce inflammatory infiltration, and improve dysfunction (Table 1).

 Related pathways of inflammatory responses in cartilage injury

With the deepening of research, the pathogenesis and treatment of cartilage injury can be better explored from the aspect of inflammatory pathways. The traditional view is that inflammatory response is the result of cartilage injury, but now more and more studies have shown that the activation of inflammatory pathways may be the initial factor of cartilage injury. For example, the well-known NF-κB pathway, MAPK/NF-κB, AKT/mTOR, IL-1β/IL-6/STAT3 pathway, etc. (33–35).

NF-κB

Moreover, recent studies have shown that inhibition of NF-κB pathway can significantly reduce IL-1β-induced chondrocyte apoptosis, thereby reducing cartilage damage reover, SNIP1 has been shown to allevia age by inhibiting the NF-κB pathway (reducing the phosphorylation and nuclear translocation of p65), reducing the release of TNF-α/IL-6 and extracellular matrix (ECM) degradation. It further proves that NF-κB pathway is also a central driver in the inflammatory response of cartilage injury (36). Recent studies have shown that FABP4 directly induces the expression of catabolic markers in chondrocytes by activating the NF-κB pathway, which promotes cartilage degeneration and osteoarthritis. This study provides a new idea for studying the pathogenesis of OA (37) (Figure 2).

 MAPK/NF-κB

Some studies have found that inhibiting the activation of MAPK/NF-κB pathway in chondrocytes can reduce the release of proinflammatory factors, oxidative stress and extracellular matrix degradation induced by IL-1β. At the same time, it reprograms the polarization of macrophages to improve the joint microenvironment, thereby delaying the progression of osteoarthritis (38). Moreover, inhibition of the MAPK/NF-κB pathway has been shown to reduce the phosphorylation of p38 and nuclear translocation of p65, and reduce the expression of IL-1β-induced inflammatory factors (iNOS/COX-2) and catabolic enzymes (MMP3/MMP13/ADAMTS5), thereby protecting collagen II and aggrecan and alleviating cartilage damage (39) (Figure 2).

 AKT/mTOR

Experimental studies have shown that Fostamatinib inhibits IL-1β-induced inflammation and extracellular matrix degradation by blocking the MAPK/NF-κB pathway, while activating the AKT/mTOR pathway to promote chondrocyte autophagy, thereby maintaining cartilage homeostasis and reducing temporomandibular joint osteoarthritis injury (34). lncRNA OIP5-AS1 has been shown to up-regulate PPAR-γ by binding to Fused in sarcoma (FUS), activate AMPK/AKT/mTOR signaling axis, enhance mitautophagy, eliminate LPS-induced reactive oxygen species (ROS) and improve mitochondrial dysfunction (membrane potential recovery/calcium homeostasis). Thus, it can reduce the inflammatory damage of chondrocytes and the degradation of extracellular matrix, and delay the progression of osteoarthritis (40) (Figure 2).

In summary, current studies have identified that NF-κB, MAPK/NF-κB, AKT/mTOR and other inflammatory pathways are the initial drivers of cartilage injury, and mediate cartilage degeneration by regulating inflammatory factors (TNF-α/IL-6), catabolic enzymes (MMPs/ADAMTS5) and autophagy imbalance. However, the unknown mechanism of interaction between pathways, the low efficiency of targeted drug delivery, and the lack of individualized treatment strategies are currently the difficulties that need to be solved. In the future, there is hope to improve the targeting by developing multi-pathway synergistic inhibitors, combining nanoparticles, and exploring gene/epigenetic precise intervention.

 The relationship between oxidative stress and osteoporosis and cartilage damage The role of oxidative stress in osteoporosis and its related pathways Role of oxidative stress response in osteoporosis

Oxidative stress refers to the imbalance between oxidative and antioxidant systems in the body, which leads to excessive production of reactive oxygen species (ROS) beyond the body’s ability to clear, resulting in damage to cells and tissues. On the one hand, ROS can directly damage osteoblasts and osteocytes, leading to dysfunction and apoptosis. On the other hand, oxidative stress can also promote bone resorption by activating osteoclasts, both of which will aggravate osteoporosis (41). Among them, the common key nodes include superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), RUNX2, OPN and glutathione (GSH) (9, 42–44). Some studies have shown that inhibiting oxidative stress-mediated bone metabolism can alleviate the symptoms of osteoporosis in vivo (45). Moreover, studies have found that ROS can affect the expression of miRNA by activating transcription factors, and miRNA can regulate the production of ROS and the inflammatory process (46). In other words, ROS not only affects osteoporosis due to its own production, but also affects the inflammatory response, thus causing double damage to osteoporosis. It has also been found that activation of AKT-dependent Nrf2 cascade protects osteoblasts from oxidative stress (47). And studies have found that, Down-regulation of HIF-1αpathway can reduce ROS accumulation, alleviate oxidative stress, prevent and inhibit iron overload-induced osteoblast dysfunction, promote bone formation, and alleviate OP (48) (Table 2).

Oxidative stress factors associated with osteoporosis and cartilage damage.

Osteoporosis related oxidative factors Oxidative factors associated with cartilage damage
Name Mechanism of action Name Mechanism of action
ROS Activation of NF-κB and MAPK pathways promotes osteoclast differentiation;Inhibition of osteoblast differentiation (downregulation of Wnt/β-catenin pathway) ROS Activation of NF-κB pathway and up-regulation of MMP-13/ADAMTS-5;Induced chondrocyte apoptosis (via p38 MAPK)
H2O2 Oxidative FOXO transcription factor, leading to apoptosis of osteoblasts;Activation of Nox4 (NADPH oxidase), exacerbates oxidative stress H2O2 Oxidation of collagen II and proteoglycans destroys the matrix structure;Inhibition of SOX9 expression (reduced collagen synthesis)
MDA Disruption of cell membrane integrity leads to osteocyte apoptosis;Inhibition of collagen cross-linking and reduction of bone toughness MDA Cross-linked collagen fibers reduce cartilage elasticity;Activation of NLRP3 inflammasome (promoting IL-1β release)
SOD2 Removal of O2– → H2O2 from mitochondria SOD2 Conversion of O2– to H2O2 (mitochondrial protection)
GPx Degradation of H2O2 and lipid peroxides (GSH-dependent) GPx Degradation of H2O2 and lipid peroxides (GSH-dependent)
GSH Directly neutralize ROS and maintain REDOX balance Nrf2 Regulation of antioxidant genes (HO-1, NQO1)
Related pathways of oxidative stress response in osteoporosis

Although the current research on the key nodes of oxidative stress has matured, more potential therapeutic targets and disease intervention strategies can be found through further research on the signaling pathways. Conventional oxidative stress pathways include Wnt/β-catenin, PI3K/Akt, AMPK and Nrf2/Keap1 (49–52).

Nrf2/Keap1

Some studies have found that the antioxidant pathway is activated by up-regulating the antioxidant protein Nrf2 and inhibiting its negative regulator Keap1. This inhibits the NLRP3 inflammasoma-mediated pyroptosis of osteoblasts, thereby protecting bone formation ability and ameliorating osteoporosis caused by diabetes (53). Some researchers have also found that Mangiferin activates the Nrf2 pathway by directly binding to Keap1, and then upregulates the SLC7A11/GPX4 antioxidant axis, thereby inhibiting ferroptosis in osteoblasts, ultimately promoting bone formation and alleviating osteoporosis (54) (Figure 3).

Pathways associated with oxidative stress in osteoporosis and cartilage damage (Nrf2/Keap1: Keap1 was a negative regulator of Nrf2; Nrf2 nuclear translocation activates antioxidant enzyme genes such as HO-1/NQO1, scavenges ROS and inhibits pyroptosis. Nrf2/HO-1: the core antioxidant pathway; The activities of SOD/CAT/GPX enzymes were up-regulated to form a ROS scavenging cascade. Wnt/β-Catenin regulates osteoblast differentiation and bone matrix secretion; Targeted activation can promote bone formation (e.g., icariin). PI3K/Akt: bidirectional regulation of oxidative stress and inflammation; After activation, it promotes NF-κB signal transduction and forms a vicious cycle of inflammation-ROS. ROS node: amplifies inflammation by activating the NF-κB/MAPK pathway; Direct attack on chondrocyte membrane lipids leads to mitochondrial dysfunction.) (Created with BioGDP.com).

Diagram illustrating various cell signaling pathways. It includes elements like Wnt, PI3K, ROS, KEAP1, and Cdc42/Rac. Arrows and lines represent activation, inhibition, and regulation of transcription, leading to protein synthesis and cellular responses to stress. Key proteins such as TCF/LEF, NRF2, and SIRT1 are also shown interacting with the pathways. Wnt/β-Catenin

The Wnt/β-Catenin signaling pathway plays an important role in bone matrix secretion and bone remodeling by precisely regulating osteoblast differentiation. The imbalance of their activities can lead to bone diseases. Targeted activation of this pathway can promote osteogenic differentiation, becoming a key mechanism for anti-osteoporosis therapy, such as natural compound therapy (55).With the continuous development of science and technology, researchers have found that miR-223-3p can block the activation of Wnt/β-Catenin signaling pathway by targeting the inhibition of FHL1 protein expression, thereby inhibiting the differentiation of BMSC into osteoblasts and ultimately accelerating the progression of osteoporosis (56). This study provides a new idea for the prevention and treatment of osteoporosis in the future (Figure 3).

 PI3K/Akt

Some researchers have found that P2X7 receptor promotes osteoclast differentiation (MMP-9/CK/NFATc1) and bone resorption by activating the PI3K/Akt pathway and phosphorylating the downstream GSK3β to accelerate bone mass loss. It can cause the occurrence and aggravation of osteoporosis, and the above effects may be reversed by inhibiting the pathway (57). In addition, some experimental studies have found that Luteolin can inhibit oxidative stress, improve mitochondrial function, and block GSDME-mediated pyroptosis of osteoblasts by activating PI3K/Akt pathway, thereby maintaining bone formation ability and alleviating postmenopausal osteoporosis (58) (Figure 3).

In summary, an in-depth understanding of the relationship between oxidative stress and osteoporosis will help to reveal the pathogenesis of osteoporosis and provide a theoretical basis for the development of new treatment methods. Secondly, the detections markers, such as CAT and SOD, can provide useful reference for the early diagnosis and disease evaluation of osteoporosis. In addition, the development of drugs or nutrients with antioxidant effects, such as vitamin C, vitamin E, melatonin, etc., may provide a new way for the prevention and treatment of osteoporosis (59, 60).

 The role of oxidative stress in cartilage injury and its related pathways Role of oxidative stress response in cartilage injury

In cartilage, oxidative stress response can lead to cartilage damage through a variety of pathways. Firstly, ROS can directly attack the cell membrane of chondrocytes, leading to lipid peroxidation of the cell membrane and destroying the integrity and function of the cell membrane (61–63). This will worsen the living environment of chondrocytes and affect their normal metabolism and function. Studies have shown that inhibiting the expression of FOXO3 and its related downstream antioxidant kinases can lead to the accumulation of ROS and aggravate the oxidative stress injury of nucleus posus cells (NPC), which aggravates the degeneration of intervertebral disc (62). However, some researchers have found that glycopeptide hydrogels implanted in the body can improve the generation rate of new cartilage by using the characteristics of nuclear factor erythroid 2 related factor 2 (Nrf2), which can activate the related endogenous antioxidant pathway (64). However, in studies targeting non-traumatic osteonecrosis of the femoral head, researchers found that lactate dehydrogenase (LDH), malondialdehyde (MDA), and ROS were significantly enhanced in chondrocytes (65) (Table 2).

 Related pathways of oxidative stress response in cartilage injury

Based on the latest research, oxidative stress directly regulates cartilage injury through the Nrf2/HO-1, Keap1/Nrf2/HO-1, and Nrf2/PINK1 antioxidant pathways, and indirectly aggravates injury by activating the MAPK/NF-κB inflammatory pathway (66–68).

Nrf2/HO-1

Some researchers have found that SIRT6 blocks ferroptosis in chondrocytes by activating the Nrf2/HO-1 pathway and inhibiting the expression of endoplasmic reticulum stress-related proteins. This mechanism alleviates IL-1β-induced inflammatory response and cell death, and ultimately alleviates osteoarthritis cartilage destruction (69). Researchers found that curcumin activated the NRF2/HO-1 pathway and up-regulated antioxidant enzymes such as superoxide dismutase to scavengers superoxide free radicals. Combined with catalase (CAT), the downstream hydrogen peroxide (H2O2) is further degraded to form a ROS scavenging cascade. This synergistic effect significantly enhanced the ability of scavenging reactive oxygen species, inhibited IL-1β-induced chondrocyte apoptosis, and alleviated oxidative stress induced cartilage damage. In vivo experiments confirmed that the combination of two drugs was more effective than single drug in promoting the expression of ROS scavenging enzymes and protecting articular cartilage (70) (Figure 3).

 Keap1/Nrf2/HO-1

Experimental studies have found that fenuiramine (TG) can relieve the inhibition of Nrf2 by down-regulating Keap1, activate Nrf2 nuclear translocation, up-regulate the expression of antioxidant enzymes such as HO-1/NQO1, significantly eliminate ROS, and inhibit IL-1β-induced chondrocyte apoptosis, senescence, and extracellular matrix degradation (71). Moreover, some studies have found that the activation of Keap1/Nrf2/HO-1 pathway can not only remove ROS (MDA↓) by up-regulating GSH/SOD/CAT, but also inhibit CYP2E1 to reduce the generation of free radicals. The expression of TNF-α/IL-1β/IL-6 was reduced by blocking the phosphorylation of MAPK/NF-κB. At the same time, inflammation inhibition further reduces oxidative stress and forms an “antioxidation-anti-inflammatory” positive feedback loop (67) (Figure 3).

 PI3K/Akt

Studies have found that high glucose can inhibit autophagy by activating the PI3K/Akt/mTOR pathway, leading to mitochondrial dysfunction and promoting the release of inflammatory factors COX-2/IL-1β. Conversely, SIRT3 can inhibit PI3K/Akt phosphorylation, restore autophagy to remove damaged mitochondria, block ROS inflammatory cycle, and reduce chondrocyte apoptosis and matrix degradation. These results reflect the bidirectional interaction between PI3K/Akt pathway and oxidative stress and inflammatory response in cartilage injury (72). Studies have shown that the activation of PI3K/Akt pathway can promote the downstream NF-κB signal transduction, leading to the expression of pro-inflammatory factors (IL-6, TNF-α), inflammatory enzymes (iNOS, COX-2) and matrix degradation enzymes (MMP3, MMP-13). Inflammation-induced oxidative stress products such as reactive oxygen species (ROS) can further stimulate the activation of PI3K/Akt pathway, forming a positive feedback loop that continuously amplifies inflammatory response and cartilage destruction (73) (Figure 3).

In summary, Nrf2 pathway (HO-1/Keap1) has a clear antioxidant protective effect, and PI3K/Akt pathway reveals a two-way interaction between oxidative stress and inflammation (activation forms a vicious cycle). However, there is a lack of research on the interaction mechanism between pathways, the specific targets of PI3K/Akt in regulating oxidative stress are vague, and the evidence of clinical transformation is lacking. In the future, it is necessary to further analyze the multi-pathway synergistic network and develop dual regulatory strategies targeting the PI3K/Akt-NF-κB/Nrf2 axis to promote clinical translation.

 The relationship between traditional Chinese medicine in the treatment of osteoporosis and cartilage injury

With the continuous development of TCM in recent years, its advantages in the treatment of osteoporosis and cartilage damage are more and more prominent. Its advantages are multi-target regulation, natural safety and treatment of both symptoms and root causes. Among them, some studies have shown that icariin in Epimedium can inhibit osteoclast generation through Cullin 3/Nrf2/OH signaling pathway, thereby relieving the bone aging process (74). Kaempferol in Epimedium inhibits autophagy and ameliorates abnormal proliferation and inflammation in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) by activating MAPK8/NOD-like receptor protein 3 (NLRP3) signaling pathway (75). In the study of Rhizoma Drynariae (TFRD), it was found that TFRD could not only improve the symptoms of osteoporosis by increasing bone trabeculae and bone density by promoting bone formation and inhibiting bone resorption (76), but also effectively inhibit the inflammatory response of fibroblast-like synoviocytes. The abnormal activation of ROS, MAPK, PI3K/AKT and NF Kappa B signaling pathways can be inhibited to improve arthritis (77). In the study of Salvia miltiorrhiza Bunge, it was found that it may improve osteoporosis by regulating autophagy and oxidative stress-mediated osteoclast differentiation through RANKL (78). It has also been found that tanshinone IIA in Salvia miltiorrhiza inhibits articular cartilage degradation by inhibiting cell apoptosis and the expression level of inflammatory cytokines, thereby alleviating cartilage damage (79). And in the study of Astragalus, the latest study found that, the LA fermenting APS can better improve calcium absorption and osteoporosis by increasing active metabolites and altering gut microbiota (80), astragalus polysaccharides could ameliorate osteoarthritis by ASK1/p38 signaling pathway through regulating thioredoxin (81). In addition to the research on single Chinese medicine, the research on Chinese medicine prescription is also increasingly in-depth, such as Bushen Zhuanggu decoction and Duhuojisheng decoction. However, due to the large number of drugs in the prescription, its mechanism of action is not clear. With the continuous development of modern technology, the development of traditional Chinese medicine extracts tends to be more mature, such as Curcumin and Hesperidin (Table 3). Future research can combine nano-agents and omics technology to improve targeting and bioavailability, so as to better break through the current limitations.

Active ingredients and mechanism of action of related TCM.

Name of TCM Active ingredient Mechanism of action
Epimedium Icariin、Epmedin A/B/C,etc Activation of Wnt/β-catenin pathway promotes osteogenesis;Inhibition of NF-κB and reduction of cartilage inflammation
Rhizoma Drynariae Naringin、Neoeriocitrin、Davallic Acid,etc It regulates OPG/RANKL balance and inhibits osteoclasts;Inhibition of MMP-3/13 can reduce cartilage matrix degradation
Salvia miltiorrhiza Bunge Tanshinone IIA、Salvianolic acid B,etc Blockade of RANKL signaling and inhibition of osteoclasts;Scavenging ROS and protecting chondrocyte
Astragalus Astragalus polysaccharide、Astragaloside IV,etc Activation of ERK1/2 pathway can promote osteogenesis;IL-1β was inhibited to reduce cartilage degradation
Psoralea corylifolia Linn Psoralen、Isopsoralen,etc It can promote the expression of BMP-2 and enhance osteogenesis;Inhibition of IL-6/TNF-α to protect cartilage
Eucommia ulmoides Eucommiol、Geniposide,etc Up-regulation of osteocalcin (OCN) promotes bone mineralization;Inhibition of COX-2/PGE2 can reduce cartilage inflammation
Angelica sinensis Ferulic acid、Ligustilide,etc Inhibition of TRAP activity in osteoclasts;Down-regulation of MMP-3/9 can delay cartilage degeneration
The relationship between oxidative stress and inflammatory response and between osteoporosis and cartilage injury

Oxidative stress and inflammation are two closely related physiological and pathological processes, which promote each other through complex molecular mechanisms and jointly participate in the occurrence and development of many diseases (82, 83). Oxidative stress refers to the imbalance between reactive oxygen species (ROS) and antioxidant defense system in the body, leading to excessive accumulation of ROS (84). However, inflammatory response is a defensive response of the body to injury or infection, which is characterized by the release of proinflammatory cytokines (such as TNF-α and IL-6) and the infiltration of inflammatory cells (85). Studies have shown that there is a bidirectional regulatory relationship between these two processes, forming a vicious cycle that exacerbates tissue damage.

On the one hand, oxidative stress can trigger or amplify the inflammatory response by activating NF-κB and MAPK signaling pathways and promoting the expression of pro-inflammatory factors (86). For example, ROS can oxidative modify inflammation-related proteins, enhance their activity or stability, and further exacerbate inflammation. On the other hand, activated immune cells in the inflammatory response, such as neutrophils and macrophages, produce large amounts of ROS through respiratory burst, leading to elevated levels of oxidative stress (87). This interaction is particularly significant in atherosclerosis, diabetes, neurodegenerative diseases, and chronic inflammatory diseases (88, 89).

In addition, antioxidant therapy (such as vitamin C and E supplementation or the use of NADPH oxidase inhibitors) can reduce the inflammatory response, while anti-inflammatory drugs (such as glucocorticoids) can also indirectly reduce the level of oxidative stress, suggesting that combined intervention against the two may be an important strategy for the treatment of related diseases in the future (90–92). However, ROS are also involved in cell signaling and immune defense in the physiological state, so how to precisely regulate the oxidation-inflammation balance still needs to be further studied.

In summary, the interaction between oxidative stress and inflammatory response is a common pathological basis for a variety of diseases, and a deep understanding of the mechanism will help to develop new targeted therapies. Future research should focus on revealing the spatiotemporal relationship between specific ROS sources and inflammatory pathways to provide more precise treatment.

Osteoporosis and cartilage damage are two common degenerative bone and joint diseases, which are common in middle-aged and elderly people (93). Although the sites of the two diseases are different, with osteoporosis mainly affecting bone tissue and cartilage damage involving articular cartilage, more and more studies have shown that the two diseases are closely related in the pathogenesis and may promote each other to accelerate the degeneration of the bone and joint system (9, 94).

Osteoporosis is characterized by decreased bone mass and destruction of bone microstructure, leading to decreased mechanical properties of bone (95). At the joint site, the osteoporosis of subchondral bone will change its mechanical support and cause abnormal stress distribution of articular cartilage, thus accelerating cartilage wear (82). In addition, osteoporosis related bone remodeling abnormalities (such as increased osteoclast activity) may promote the release of proinflammatory factors (such as IL-1β and TNF-α) (96), further aggravating the degradation of cartilage extracellular matrix and inhibiting cartilage repair.

After cartilage injury, the joint mechanical environment changes, leading to uneven local stress distribution, which may affect the metabolic balance of subchondral bone and promote increased bone resorption (97). At the same time, chronic low-grade inflammation accompanying cartilage degeneration can activate osteoclasts and accelerate bone loss (63). It is suggested that cartilage injury may affect bone metabolism through both inflammatory and mechanical factors.

In summary, osteoporosis and cartilage injury may share certain pathological mechanisms, such as oxidative stress, inflammation and abnormal regulation of Wnt/β-catenin signaling pathway. Thus, treatments that target these common pathways, such as antiinflammatory drugs, bisphosphonates, or stem-cell therapies, may improve both conditions. In addition, mechanical interventions can enhance bone strength and promote cartilage nutrition, such as moderate exercise, thereby delaying disease progression.

 Conclusion

In general, osteoporosis and cartilage damage are closely related in the pathogenesis, and inflammatory response and oxidative stress are the common core pathological processes of both. Inflammatory factors (such as TNF-α and IL-1β) destroy bone metabolic balance and accelerate cartilage degradation through NF-κB and other pathways, while oxidative stress aggravates osteoblast dysfunction and chondrocyte damage through ROS. The two reinforce each other, forming a vicious circle. In addition, the weakened mechanical support caused by osteoporosis further aggravates cartilage burden, while cartilage damage in turn exacerbates bone resorption through inflammatory feedback. For these common mechanisms, combined anti-inflammatory, antioxidant and mechanical interventions (such as exercise) may be effective treatment strategies. Future research should further elucidate the role of mechanical factors in cartilage homeostasis, while advancing the development of multi-pathway combination therapies (e.g., integrating anti-inflammatory, antioxidant, and mechanical regulation) to provide novel strategies for preventing and treating age-related bone and joint disorders.

 Author contributions

QL: Writing – original draft, Conceptualization. XZ: Writing – original draft. AW: Formal Analysis, Writing – original draft. TH: Writing – original draft, Software. JZ: Writing – original draft, Software. SZ: Writing – original draft, Data curation. LZ: Writing – review & editing. WW: Funding acquisition, Conceptualization, Writing – review & editing, Resources.

 Conflict of interest

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.

 Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Edited by: Q Wang, Guangzhou University of Chinese Medicine, China

Reviewed by: Pengfei Yu, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, China

Liu Kang, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, China