Metabolism-Related Adipokines and Metabolic Diseases: Their Role in Osteoarthritis

Qian Zhang; Yi Xuan Zhao; Long Fei Li; Qian Qian Fan; Bin Bin Huang; Hong Zhen Du; Chen Li; Wei Li

doi:10.2147/JIR.S499835

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Metabolism-Related Adipokines and Metabolic Diseases: Their Role in Osteoarthritis

Authors Zhang Q, Zhao YX, Li LF, Fan QQ, Huang BB, Du HZ, Li C , Li W

Received 8 October 2024

Accepted for publication 31 December 2024

Published 25 January 2025 Volume 2025:18 Pages 1207—1233

DOI https://doi.org/10.2147/JIR.S499835

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Ning Quan

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Metabolism-related adipokines and diseases in osteoarthritisa – Video abstract [499835]

Qian Zhang,^1,^* Yi Xuan Zhao,^1,^* Long Fei Li,² Qian Qian Fan,³ Bin Bin Huang,¹ Hong Zhen Du,¹ Chen Li,³ Wei Li³

¹School of Special Education and Rehabilitation, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; ²Cerebrovascular Disease Ward, The First People’s Hospital of Ping Ding Shan, Pingdingshan, Henan, People’s Republic of China; ³Department of Rehabilitation Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Wei Li; Chen Li, Department of Rehabilitation Medicine Binzhou Medical University Hospital, No. 661 huanghe 2nd Road, Binzhou, Shandong, People’s Republic of China, Email [email protected]; [email protected]

Abstract: Osteoarthritis (OA) affects several joints but tends to be more prevalent in those that are weight-bearing, such as the knees, which are the most heavily loaded joints in the body. The incidence and disability rates of OA have continued to increase and seriously jeopardise the quality of life of middle-aged and older adults. However, OA is more than just a wear and tear disease; its aetiology is complex, and its pathogenesis is poorly understood. Metabolic syndrome (MetS) has emerged as a critical driver of OA development. This condition contributes to the formation of a distinct phenotype, termed metabolic syndrome-associated osteoarthritis (MetS-OA),which differs from other metabolically related diseases by its unique pathophysiological mechanisms and clinical presentation. As key mediators of MetS, metabolic adipokines such as leptin, lipocalin, and resistin regulate inflammation and bone metabolism through distinct or synergistic signaling pathways. Their modulation of inflammatory responses and bone remodeling processes plays a critical role in the pathogenesis and progression of OA. Due to their central role in regulating inflammation and bone remodeling, metabolic adipokines not only deepen our understanding of MetS-OA pathogenesis but also represent promising targets for novel therapeutic strategies that could slow disease progression and improve clinical outcomes in affected patients.

Keywords: osteoarthritis, metabolic syndrome, adipokines

Introduction

OA is a chronic degenerative disease characterised by pain, joint stiffness, and swelling, mostly in the knee joint and hip joint.^1–4 There are gender differences in the prevalence and incidence of OA, with women generally being at higher risk than men, especially post-menopausal women around the age of 50; age is also an influencing factor in OA, with the incidence of OA of the knees and hips increasing with age for both men and women. Furthermore, the socio-economic level is an influencing factor in the incidence of OA, with poorer areas, such as rural areas, tending to have higher incidence rates than cities do.^5–9 The prevalence and burden of OA are growing exponentially and are expected to affect 78.4 million people by 2040.^10,11 As China gradually enters an ageing society, OA can seriously affect the quality of life of patients and impose a huge social and economic burden.¹² Current treatments for OA are largely limited to steroidal or non-steroidal anti-inflammatory drugs, which only relieve pain and inflammatory symptoms.¹³ As a result, there is no effective treatment for the disease at this time.¹⁴

MetS is a multifaceted condition defined by a cluster of metabolic abnormalities, including obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia.¹⁵ While traditionally recognized as a major risk factor for cardiovascular diseases and diabetes, emerging evidence highlights its critical role in the pathogenesis and progression of OA.^15–17 MetS-related metabolic disturbances adversely affect multiple joint tissues, such as cartilage, bone, and synovium, through mechanisms that involve chronic low-grade inflammation, oxidative stress, and imbalances in adipokine regulation.^15–17These interconnected processes collectively contribute to the initiation and exacerbation of OA, positioning MetS as a significant driver of disease development. The concept of metabolic syndrome-associated MetS-OA has recently been introduced, despite the high prevalence of MetS-OA, its underlying pathogenic mechanisms remain poorly understood.¹⁶ Metabolic syndrome has been shown to promote the release of inflammatory cytokines, particularly adipokines, which play a pivotal role in establishing a chronic low-grade inflammatory state, driving cartilage degeneration, and disrupting the balance of the intra-articular environment.^16,18 These insights underscore the critical contribution of adipokines to the pathogenesis of MetS-OA.¹⁶

Adipokines, primarily secreted by white adipose tissue, are signaling molecules that regulate inflammation and metabolic processes, with dysregulation linked to various diseases, including OA.^19–21 In OA, they are central mediators of pathogenesis, contributing to chronic inflammation, cartilage degradation, and bone remodeling imbalances through shared inflammatory and metabolic pathways such as NF-κB, PI3K/Akt, and MAPK.^22,23 Recent clinical studies have highlighted their dual roles in OA progression, with some exacerbating the disease while others exhibit protective effects. This duality not only establishes adipokines as key contributors to OA pathophysiology but also underscores their potential as diagnostic biomarkers and therapeutic targets. Emerging targeted therapies for specific adipokines offer promising opportunities to modulate their activity, paving the way for personalized treatment strategies that address both inflammatory and metabolic components of OA and potentially transforming the management of this complex disease.

Further research is needed to confirm these relationships and investigate the role of adipose tissue in OA development. This review focuses on the impact and mechanisms of metabolic diseases and adipokines on OA onset and progression (Figure 1).

Figure 1 Metabolic diseases and adipokines influence the progression of OA through regulating inflammation and matrix degradation.

Metabolic Syndrome

MetS is a global health problem that is increasing globally and will account for approximately 1/3 of the world’s population by 2022, making it a major public health problem.^24–26 It is usually made up of four components: hyperglycaemia, hypertension, dyslipidaemia, and obesity.^27–29 The relationship between MetS and OA has been extensively studied (Figure 2).Some studies argue that metabolism minimally impacts OA, with one study showing no significant effect of MetS on OA incidence after adjusting for body mass index (BMI).³⁰ Conversely, other research suggests that MetS contributes to OA by increasing systemic inflammatory mediators from adiposity.³¹ Moreover, in patients aged 18–78 years with OA, those with MetS develop OA earlier, have more extensive pathology, increased inflammation, and increased joint pain than do those without it.^32,33 MetS manifests in a variety of ways, depending on the components that make up the syndrome,³⁴ making its early recognition particularly important. In the context of economic development and improved living standards, the number of patients with MetS has increased dramatically worldwide.^35,36 Therefore, there is a need to explore the links and mechanisms between MetS and OA to facilitate better prevention and treatment of OA.

Figure 2 A Comprehensive Overview of OA Pathophysiology Linked to Metabolic Diseases: Mechanisms of Onset. This figure illustrates the mechanisms by which MetS contributes to OA development through shared pathways of inflammation, oxidative stress, and metabolic dysregulation: Obesity: Drives cartilage degradation and joint instability via pro-inflammatory cytokines (IL-6, TNF-α), ROS, and increased joint loading. DM: Amplifies oxidative stress and inflammation through AGEs and ROS while reduced H2S levels and impaired collagen synthesis exacerbate cartilage degeneration and joint instability. HT: Activates renin-angiotensin, endothelin, and Wnt-β-catenin pathways, leading to subchondral bone calcification and remodeling imbalance. DL: Induces chronic inflammation and oxidative stress, disrupting cartilage homeostasis and accelerating OA progression. OP: Weakens subchondral bone, resulting in cartilage calcification, biomechanical imbalance, and rapid OA progression.

Relationship Between Obesity and OA

Obesity, a hallmark of MetS, is characterized by excessive fat accumulation. Over the past 50 years, its prevalence has risen steadily worldwide, with more than 2 billion individuals expected to be affected in the near future.^37,38 As a major global health challenge, obesity has emerged as a significant risk factor for OA progression through adipose tissue-dependent inflammation.^39–43 BMI, the primary clinical and research metric for measuring obesity, is positively correlated with OA risk. Specifically, individuals with a BMI greater than 30 face a two-thirds lifetime risk of OA and a doubled risk of asymptomatic OA.^44,45 While mechanical joint overload caused by a high BMI has long been considered a primary driver of OA,^46–49 it fails to fully explain the high prevalence of OA in non-weight-bearing joints, such as the hands.⁴⁵ Recent evidence highlights the critical role of obesity-associated systemic inflammation and metabolic dysregulation in OA pathogenesis.⁵⁰ In obesity, adipose tissue undergoes inflammatory remodeling, marked by a significant increase in pro-inflammatory macrophage infiltration. These macrophages release cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), disrupting chondrocyte homeostasis and accelerating cartilage degradation.^51–55 Concurrently, elevated leptin levels in synovial fluid enhance the interaction between chondrocytes and synovial fibroblasts, further amplifying IL-6 production and exacerbating local inflammatory responses.^56,57 This adipose tissue-driven inflammatory cascade links systemic metabolic disturbances to localized joint pathology, establishing a critical connection between obesity and OA.

By elucidating the interplay between systemic inflammation, local joint damage, and metabolic dysregulation, this framework underscores the central role of adipose tissue-dependent inflammation in OA. These insights deepen our understanding of obesity-induced OA and provide a robust foundation for developing targeted interventions that address both the inflammatory and metabolic components of this complex disease.

Relationship Between Diabetes Mellitus and OA

Diabetes mellitus (DM) is a prevalent non-communicable disease characterized by systemic metabolic dysregulation caused by an imbalance between risk and protective factors.^58,59 Studies have demonstrated a strong association between DM and the onset and progression of OA.⁵⁸ Compared to non-diabetic OA patients, those with DM typically exhibit greater pain intensity and poorer physical and mental health.⁶⁰ While numerous studies have identified a significant link between DM and OA—such as an increased risk of joint replacement surgery—the exact mechanisms underlying this relationship remain unclear and controversial.^61,62

Emerging evidence indicates that DM exacerbates OA progression through three primary mechanisms: chronic inflammation, joint structure degeneration, and joint instability.⁶³ Elevated levels of IL-6 and Progranulin(PGRN) in OA joint tissues of DM patients suggest that cartilage in these individuals is more susceptible to pro-inflammatory stress, leading to heightened inflammatory responses.⁶⁴ Furthermore, increased reactive oxygen species (ROS) in DM-associated OA not only stimulate the production of inflammatory mediators such as IL-1β but also inhibit collagen synthesis in cartilage, accelerating cartilage degradation.^65–67 This oxidative stress further disrupts cartilage homeostasis, potentially due to decreased levels of protective factors such as hydrogen sulfide (H2S) and nuclear factor erythroid 2-related factor 2 (Nrf-2).⁶⁸ DM also contributes to neuromuscular deficits, which exacerbate joint instability and increase cartilage friction, thereby further advancing OA progression.⁶⁸ These DM-induced structural changes amplify joint instability, accelerating disease development. However, some studies dispute the direct relationship between DM and OA, arguing that DM is not an independent risk factor for OA. Such discrepancies may arise from differences in study design, patient populations, and the multifactorial etiologies of both diseases.^69–71

To resolve these controversies, future research should clarify the molecular mechanisms linking DM to OA, particularly through inflammatory and oxidative stress pathways. Studies should examine how DM differentially affects weight-bearing and non-weight-bearing joints and explore variations in OA progression across DM types. Addressing these gaps will enhance our understanding of the DM-OA relationship and facilitate the development of targeted therapies addressing shared metabolic and inflammatory pathways.

Relationship Between Hypertension and OA

Hypertension (HT) affects more than 1 billion adults worldwide, and its prevalence is on the rise.⁷² HT has been found to be significantly associated with the development of OA, and OA prevalence in patients with hypertension is approximately 40%.^73,74 Gender is an influential factor in the relationship between HT and OA, with Lawrence suggesting that HT is associated with OA in women.⁷⁵ Yang et al concluded that HT is linked to an increased OA risk in men, potentially due to joint structural degeneration and biochemical pathways.⁷⁶ Increased subchondral bone calcification was found in hypertensive OA animals compared to normal OA animals,⁷⁷ and a meta-analysis reported a stronger correlation between hypertension and knee OA on imaging, suggesting that hypertension is strongly associated with structural damage to the OA.⁷⁸ Furthermore, HT activates the renin-angiotensin and endothelin systems, affecting the Wnt-β-catenin signalling pathway and potentially influencing joint disease.⁷⁶ The causal link between OA and HT is unclear, and future research should clarify how HT impacts OA joints.

Relationship Between Dyslipidaemias and OA

Dyslipidaemias (DLs) are typically characterised by abnormal levels of serum cholesterol, triglycerides, or both, as well as abnormal levels of associated lipoprotein species.⁷⁹ The link between DL and OA is debated. Several studies indicate DL may elevate OA risk,^80–83 likely due to its impact on body homeostasis and association with chronic inflammation and oxidative stress.^84,85 Conversely, Inoue found no significant of DL on hand OA risk.⁸⁶

Relationship Between Osteoporosis and OA

Osteoporosis (OP) is a systemic skeletal disease increasingly prevalent with aging, marked by reduced bone strength and microarchitectural deterioration.⁸⁷ Both OP and OA are complex, multifactorial disorders lacking a complete cure, significantly contributing to pain and socio-economic burdens worldwide. It is imperative to explore their interrelation and devise new therapeutic strategies.^88–90 Recent studies highlight OA’s susceptibility to subchondral fragility, potentially leading to the emergent concept of OP-OA, meriting further attention.⁹¹ Although a negative correlation between OP and subsequent OA development is suggested by most research, including a two-sample MR analysis indicating that OP may lower OA incidence, this relationship remains debated.^92,93 Further findings indicate that OP-OA patients experience faster OA progression due to abnormal subchondral bone remodelling, increased cartilage calcification and damage, and biomechanical deterioration.^94–96 However, the exact mechanisms linking these conditions require more investigation.

The study of metabolic diseases associated with OA has transformed our understanding of its pathogenesis. It is now recognized that OA extends beyond mere joint “wear and tear” due to overloading; it is a chronic inflammatory condition influenced by systemic metabolism, inflicting both physical and psychological stress on patients, and imposing a significant economic burden on society. Consequently, exploring the link between metabolic diseases and OA to identify novel treatment strategies is a promising approach. The various roles of metabolic diseases in the context of OA have been discussed in Table 1.

Table 1 Major Epidemiological Studies of Metabolic Diseases Associated with OA

Metabolic Diseases and OA Pathogenesis

Obesity, DM, HT, DL, and OP collectively drive the onset and progression of OA through convergent mechanisms involving inflammation, oxidative stress, and metabolic dysregulation. Together, these MetS not only contribute to structural joint damage but also reveal the intricate, multifaceted complexity of OA pathogenesis.

Pro-inflammatory factors associated with obesity, such as IL-6, TNF-α, and leptin, aggravate cartilage degradation and local inflammation through the activation of NF-κB and PI3K/Akt signaling pathways.^51–55 In DM, the accumulation of advanced glycation end-products (AGEs) and elevated levels of ROS amplify oxidative stress in cartilage while suppressing protective mechanisms mediated by nuclear factor Nrf-2 and H2S.⁶⁸ This interplay accelerates cartilage deterioration and exacerbates joint instability. Hypertension contributes to OA-related structural damage by activating the Wnt-β-catenin pathway, which promotes subchondral bone calcification and remodeling imbalances.^76,77 Although the precise role of dyslipidemia remains contested, chronic inflammation and oxidative stress likely mediate its contribution to OA progression.^84,85 Osteoporosis introduces the concept of “OP-OA”, emphasizing how subchondral bone fragility exacerbates cartilage calcification and biomechanical imbalances, further driving OA advancement.^93,95

Future research should focus on the differential effects of shared inflammatory and metabolic pathways in various joints and the synergistic impact of MetS components like obesity, DM, and HT. Targeting common molecular mechanisms through precision medicine approaches based on inflammatory and metabolic biomarkers can improve clinical outcomes and reduce OA’s socioeconomic burden.

Relationship Between Metabolism-Related Adipokines and OA and Their Pathways of Action

Adipokines

Adipokines are bioactive molecules secreted primarily by adipose tissue, particularly white adipose tissue, and include hormones, cytokines, and chemokines.¹⁹ These molecules function through autocrine, paracrine, and endocrine pathways to regulate a range of physiological and pathological processes, including energy metabolism, inflammatory responses, immune regulation, and insulin sensitivity.²⁰ Beyond their critical role in maintaining metabolic homeostasis, adipokines are deeply involved in the pathogenesis of various diseases, such as metabolic syndrome, cardiovascular diseases, and OA.²¹ Adipokines play a central role in the pathogenesis of OA by modulating chronic inflammation, disrupting cartilage metabolic balance, and impairing bone remodeling.²¹ These interconnected mechanisms not only accelerate joint degeneration but also underscore the pivotal role of metabolic disturbances in driving OA progression.^97–100 Furthermore, the unique contributions of adipokines, independent of mechanical loading, in obesity- and metabolic syndrome-associated OA highlight their potential as key targets for elucidating OA pathophysiology and developing innovative therapeutic strategies.^101,102 This understanding offers a comprehensive perspective on the multifaceted roles of adipokines in OA and provides a robust foundation for future research focused on personalized interventions targeting adipokines and their associated signaling pathways.

Adipokines in Osteoarthritis: Clinical Evidence and Therapeutic Implications

Recent clinical studies have demonstrated that adipokines play a pivotal role in the onset and progression of OA, particularly in the regulation of inflammation, cartilage degradation, and metabolic dysregulation. Leptin levels are significantly associated with the severity of joint pain in OA patients, likely by exacerbating inflammation-induced pain.^103,104 In contrast, adiponectin levels are reduced in late-stage OA and are inversely correlated with the severity of pain in OA patients, highlighting its potential protective role in joint health.¹⁰³ Furthermore, leptin concentrations in synovial fluid are strongly correlated with BMI and waist circumference, suggesting that obesity and metabolic syndrome accelerate OA progression through leptin-mediated mechanisms.¹⁰⁵ LCN2, a pro-catabolic adipokine, is markedly elevated in the synovial fluid and cartilage of OA patients. It enhances the activity of MMPs, promoting cartilage matrix degradation and intensifying inflammatory responses.¹⁰⁶ Similarly, visfatin levels in serum and synovial fluid are strongly associated with inflammation severity and disease progression in OA, further exacerbating joint tissue damage.¹⁰³ Resistin levels are significantly increased in the synovial fluid and serum of OA patients, accelerating OA pathogenesis by promoting extracellular matrix degradation and the release of pro-inflammatory cytokines.^103,107 Additionally, adipsin levels are significantly associated with lateral cartilage volume loss in the knee, suggesting its role in structural joint damage.¹⁰⁸ OPN levels in serum are strongly correlated with OA severity, particularly in the early stages of the disease, highlighting its potential as a biomarker for early diagnosis and intervention.¹⁰⁴ RBP4 is highly expressed in the serum and synovial fluid of OA patients, with levels significantly associated with matrix metalloproteinase (MMP) activity and pro-inflammatory cytokines, underscoring its critical role in cartilage degradation and inflammation.¹⁰⁹ Omentin-1 levels are significantly reduced in the plasma and synovial fluid of OA patients. This reduction is closely linked to joint pain, stiffness, and advanced radiographic severity, indicating a potential protective role for omentin-1 in joint health.¹¹⁰ Metrnl levels are notably lower in late-stage OA patients compared to those in earlier stages, with higher Metrnl levels in synovial fluid inversely correlated with MMP-13, a key marker of cartilage degradation.¹¹¹ These findings suggest that Metrnl may protect cartilage and mitigate inflammation. Conversely, nesfatin-1 levels are significantly elevated in the serum of OA patients, and its synovial fluid concentrations are positively correlated with pro-inflammatory cytokine IL-18, further supporting its role as a pro-inflammatory mediator.¹¹²

These findings collectively underscore that adipokines are not only critical regulators of inflammation and metabolic processes in OA progression but also represent promising diagnostic and therapeutic targets. This evidence provides a robust foundation for developing personalized treatment strategies based on adipokine levels, offering new avenues for precision medicine in OA management.

Therapeutic Potential of Adipokines in OA Treatment

Adipokines have recently emerged as promising therapeutic targets for OA, offering innovative strategies to mitigate disease progression by modulating inflammation, cartilage degradation, and metabolic dysregulation. Leptin, a pro-inflammatory adipokine, has been targeted through therapeutic approaches such as leptin receptor antagonists (eg, Allo-aca) and leptin analogs (eg, Metreleptin), which have shown potential in alleviating inflammation and addressing metabolic disorders by modulating leptin signaling pathways.^113,114 In contrast, adiponectin exhibits anti-inflammatory and chondroprotective properties. Its receptor agonist, AdipoRon, demonstrated efficacy in preclinical models by significantly reducing inflammation and preserving cartilage integrity.¹¹⁵ Similarly, visfatin, another pro-inflammatory mediator associated with OA, has been targeted using the specific inhibitor FK866, which has shown promise in suppressing inflammatory responses and represents a potential therapeutic target.¹¹⁶ Additionally, RBP4 exacerbates metabolic dysregulation in OA. The RBP4 inhibitor Fenretinide has demonstrated efficacy in mitigating metabolic disturbances, highlighting its potential as a viable treatment option for OA.¹¹⁷

These findings underscore the pivotal role of adipokines in OA pathophysiology and highlight their targeted therapeutic potential. Future research should prioritize validating these therapeutic strategies through rigorous clinical trials and evaluating their integration into precision medicine frameworks.

Leptin’s Role in OA

Leptin was first identified as a product of the ob gene in 1994;¹¹⁸ it is one of the most intensively studied adipokines, exhibiting pleiotropic properties and being mainly involved in both pro-inflammatory and bone metabolism in the pathomechanisms of OA.^119–121 Inflammatory factors play an important role in the developmental process of inflammation in OA, and IL-1, IL-6, TNFα, and IL-17 are the major cytokines involved in the pathogenesis of OA.¹²² Furthermore, some studies have found that the levels of IL-6, IL-18, and leptin are significantly correlated with the severity of post-traumatic osteoarthritis (PTOA), with the combination of IL-6 and leptin being the most discriminatory biomarker of PTOA.¹²³ IL-1β is the factor most correlated with leptin and has been extensively studied, with reports indicating that levels of both leptin and IL-1β correlate with OA.¹²⁴ Both leptin and IL-6 significantly contribute to the development of OA through the JAK-STAT pathway, a crucial element in OA pathogenesis.¹²⁵ Both molecules operate via the JAK-STAT3 pathway and play roles in OA-associated regulatory mechanisms; notably, leptin not only activates the OBRl receptor, which subsequently activates the IRS-1, PI3K, Akt, and AP-1 pathways enhancing IL-6 expression.¹²⁶ Specifically, in fibroblasts of the temporomandibular joint (TMJ-SFs), leptin engages the JAK2/STAT3 or p38 MAPK or PI3K/Akt signalling pathway and binds to the leptin-specific receptor (Ob-Rb) in the TMJ-SFs to regulate IL-6 production in vitro.¹²⁷ Furthermore, leptin, in synergy with IL-1β, prompts chondrocytes to secrete pro-inflammatory agents such as IL-6, IL-8, nitric oxide, and cyclooxygenase-2 and modulates IL-6 and IL-8 production through CD4+ T cells.^128–130 Furthermore, leptin regulates bone metabolism,^125,131 in correlation with the extent of cartilage destruction;¹³² bone metabolism is also partially affected. Inflammatory factors such as TNF-α, IL-1, and IL-6 notably induce MMP and prostaglandin production and inhibit proteoglycan and type II collagen synthesis, therefore, they play a key role in cartilage matrix degradation and bone resorption in OA.¹³³ Leptin and its downstream factors influence bone metabolism via multiple pathways, these include the induction of human ADAMTS-4 in chondrocytes through the mitogen-activated protein kinase and NF-kB signalling pathways; similarly, leptin promotes the expression of ADAMTS-4 and ADAMTS-5 in human chondrocytes, which are implicated in joint damage and the onset of OA.¹³⁴ Furthermore, leptin induces cellular senescence in OA chondrocytes by activating the mTOR pathway. Additionally, a high level of Ob-Rb expression accelerates chondrocyte senescence through the leptin pathways in OA.¹³⁵ Moreover, leptin enhances VCAM-1 expression in cartilage cells via the kinase kinases JAK2, PI3K, and AMPK, leading to accelerated cartilage degradation by promoting leukocyte and monocyte infiltration in inflamed joints.¹³⁶ Leptin increases MMP production via the JAK2 signal transducer and activator of STAT3 signalling pathway, which has a catabolic effect on OA cartilage and promotes apoptosis.¹³⁷ Finally, leptin acts through the JAK2/STAT3 signalling pathway to inhibit chondrogenicity and prevent chondrocyte apoptosis.¹³⁸ Factors downstream of leptin also play a partial role in bone metabolism, with DUSP19 downstream inhibiting chondrocyte apoptosis by dephosphorylating JNK.¹³⁹ Furthermore, LOXL3, downstream of leptin, stimulates chondrocyte apoptosis and inhibits chondrocyte autophagy.¹³⁷ Taken together, the evidence increasingly supports the potential role of leptin in OA.^122,140,141 Leptin and its receptors are critical targets for intervention in OA.¹⁴²

Lipocalin’s Role in OA

Lipocalin is a metabolism-related adipokine that regulates lipid metabolism, bone metabolism, and glucose homeostasis.^16,143 It has been found that in joints, joint adipose tissue and synovium in patients with inflammatory joint diseases are important sources of lipocalin.^144,145 Current research highlights the significant relationship between lipocalin, adipose tissue, and synovium in patients with inflammatory joint diseases. The association between lipocalin and OA remains a subject of debate, with various studies indicating that lipocalin levels are positively correlated with the development of OA and associated with OA joint pain.^{16,142,146,147} However, the underlying mechanisms by which lipocalin contributes to OA are still not fully understood and warrant further investigation.¹⁴⁸ Notably, lipocalin has been shown to correlate positively with IL-6 levels and enhance IL-6 production in synovial fibroblasts via the AdipoR1 receptor/AMPK/p38/IKK alpha beta and NF-κB signalling pathways.¹⁴⁹ This process is crucial for the pathogenesis of OA.¹⁵⁰ Lipocalin has also been found to increase VCAM-1 expression in chondrocytes through kinases such as JAK2, PI3K, and AMPK, accelerating chondrocyte degradation by inducing infiltration of leukocytes and monocytes in the inflamed joints.¹³⁶ However, other studies have indicated that lipocalin levels are negatively correlated with the severity of OA and exhibit an anti-inflammatory role in its development. Notably, lipocalin levels were observed to decrease significantly with the increasing severity of Kellgren-Lawrence OA; furthermore, the concentrations of lipocalin in blood and synovial fluid were significantly and negatively correlated with the grading of OA, leading researchers to suggest that lipocalin may serve a protective role in OA.¹⁵¹ Feng et al reviewed the protective mechanisms of lipocalin in OA in terms of both apoptosis and autophagy.¹⁴³ Liu et al found that lipocalcin activated the AdipoR1/AMPK/PKC pathway to reduce endoplasmic reticulum stress-induced apoptosis and reduced apoptosis by regulating anti-apoptotic proteins, such as Bcl-2, in mouse adipose tissues, thereby reducing the severity of OA.¹⁵² He and Duan discovered that LipocalinRon induces autophagy to mitigate cartilage calcification in OA, where He demonstrated that lipocalcin activates autophagy by mediating the AMPK-mTOR signalling pathway.²⁷ It has been proposed that lipocalcin levels do not correlate with OA development.⁵⁰ Lipofuscin-2 (Lipofectin) also plays a critical role in OA development. Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin, is identified as a novel adipokine with catabolic functions in OA.^153,154 Most studies indicate that LCN2 serves as a biomarker for cartilage degradation in OA, and complexes comprising LCN2 and MMP9 are prevalent in synovial fluid from patients with OA, contributing to matrix degradation and OA exacerbation.^155,156 However, other research has shown that while LCN2 expression is elevated in OA chondrocytes and cartilage, its overexpression does not change the expression levels of metabolic enzymes involved in matrix degradation, such as catabolic MMP3 or anabolic chondrogenic matrix molecules; thus, its increased levels are neither sufficient nor necessary for cartilage destruction in mouse OA.¹⁵⁷ These conflicting findings indicate that lipocalin and LCN2 have dual or complex roles in OA, highlighting the uncertainty of their impact on OA and underscoring the need for further investigations.

Resistin’s Role in OA

The primary source of resistin is white adipose tissue, which can be produced by macrophages as well as by cartilage itself.^96,157 Resistin plays an important role in synovial inflammation and cartilage degradation.¹⁵⁸ It is a highly potent pro-inflammatory cytokine that elevates the production of various inflammatory factors, including IL-1, TNF, and other inflammatory factors.^159,160 It has been observed that resistin facilitates the release of pro-inflammatory factors through multiple pathways.¹⁵⁹ It suppresses the expression of miR-149 and boosts the expression of TNF-α and IL-1β via MEK and ERK signalling.¹⁶¹ Nirupama et al discovered that the enhanced secretion of pro-inflammatory cytokines could also be mediated by NF-κB;¹⁶² resistin can further activate the p38-MAPK and NF-κB signalling pathways in human OA chondrocytes by binding to CAP1, fostering the expression of pro-inflammatory cytokines (CCL3, CCL4) and matrix-degrading enzymes (MMP-13, ADAMTS-4), and the release of these substances disrupts intra-articular homeostasis, leading to synovitis in knee joints and cartilage degeneration.¹⁶³ Moreover, resistin induces the expression of pro-inflammatory cytokines as well as miR-34a and miR-146a, which mediate mucin-induced oxidative stress in OA through the NF-κB pathway.¹⁵⁹ Chen et al also noted that resistin inhibits the synthesis of miR-381 via the PKCα, p38, and JNK signalling pathways, thereby influencing the expression of VCAM-1 and the adherence of monocytes to OASFs, in turn, impacts OA progression.¹⁶⁴ Some studies have found that resistin levels are positively associated with cartilage defects in OA,^165,166 promoting the generation of bone nodules.¹⁶⁷ Moreover, some researchers have found that resistin in OA bone fragments are mediated by p38 MAPK, which increases the release of pro-inflammatory mediators from osteoclasts and chondrocytes, aggravating the process of OA.²¹ Additionally, resistin is known to be a key component in the development and growth of bone mineralisation. Resistin inhibits cartilage synthesis by inducing the expression of pro-inflammatory factors such as degradative enzymes through the binding to Toll-like receptor 4 and adenylyl cyclase-associated protein 1 receptor;¹⁶⁸ moreover, resistin stimulates the significant overexpression of miR-34a, leading to apoptosis in OA chondrocytes and limiting proliferation.¹⁶⁹ Additionally, resistin promotes the expression of MMP-1 and MMP-13 in chondrocytes and increases Col2a1 mRNA, the primary collagen synthesized by these cells, thereby contributing to cartilage degradation.¹⁶⁹ Resistin has also been associated with OA and joint pain.^142,170,171 Notably, it has been found that garlic supplementation can reduce the severity of pain in women who are overweight or women with obesity suffering from OA, possibly through a reduction in resistin.¹⁷² Therefore, resistin is a critical factor in the severity of OA and cartilage degeneration of the knee joint. Resistin, as a potential biomarker of knee OA disease severity and cartilage degeneration,^173,174 is closely related to the course of OA,^146,175,176 and further in-depth studies are needed to elucidate its effect on disease outcome.

Osteopontin’s Role in OA

Osteopontin (OPN) is an extracellular matrix glycoprotein that plays an important role in the release of inflammatory factors and bone remodelling in OA.^177,178 The expression of OPN is regulated by the β-catenin/TCF-4 pathway and miRNA-127-5p.^179,180 Currently, several studies have concluded that OPN is significantly associated with the level of severity of OA.^104,181 OPN can promote the expression of metalloproteinase 13 (MMP13) in OA through the NF-kB signalling pathway,¹⁸² and its deficiency induces the secretion of pro-inflammatory cytokines, such as COL10A1, IL-1β, IL-6, IL-8, and TNF- β, which exacerbate the progression of OA.^183,184 Recent studies have shown that OPN plays a crucial role in bone metabolism.¹⁸⁵ Moreover, the overexpression of many inflammatory factors also causes an imbalance in bone metabolism. Overexpression of MMP-1 degrades the main component of type II collagen of cartilage matrix proteins in mice;¹⁸⁶ the release of TNF-α, IL-6, and IL-1β induces apoptosis of chondrocytes.¹⁸⁷ Furthermore, IL-1β, OPN, p53 upregulation, and COL1A1 and COL2A1 overexpression significantly inhibit chondrocyte viability and migration, enhance apoptosis, and induce cartilage damage.¹⁸⁸ Notably, OPN promotes NF-κB signalling, accelerates chondrocyte proliferation, and thus induces OA in rats.¹⁸⁹ Additionally, OPN-induced expression of VEGF in articular cartilage causes severe vascular invasion of cartilage and exacerbates the process of OA.¹⁹⁰

Visfatin’s Role in OA

Visfatin, an adipokine, is negatively correlated with the severity of OA.^169,191 It enhances inflammation in OA, as demonstrated by Yang, who reported increased levels of inflammatory markers such as MMP3 and MMP13 in chondrocytes.¹⁹² Furthermore, Laiguillon observed that visfatin was implicated in pro-inflammatory activation between chondrocytes and osteoblasts, significantly inducing IL-6 release.¹⁹³ Moreover, Cheleschi noted that visfatin substantially upregulated the expression of inflammatory factors, including IL-1β, IL-6, TNF-α, MMP-1, and MMP-13.¹⁵⁹ In this regard, Han and other scholars have provided a more comprehensive summary of the role of visfatin in OA: visfatin affects the differentiation of mesenchymal stem cells (MSCs) to adipocytes or osteoblasts by increasing the production of MMPs and ADAMTS, leading to alterations in cartilage and bone tissue; induces the production of inflammatory factors, such as IL-6 and TNF-α, and promotes an inflammatory state; and inhibits the production of osteoblasts. Osteoclastogenesis, which may promote bone regrowth formation in the context of inflammatory diseases.¹⁹⁴

Adipsin’s Role in OA

Adipsin, discovered in 1987, is produced by adipocytes through activation of PPAR.^195–197 Notably, lipocalin deficiency protects joint tissues from the progression of OA.¹⁹⁸ Adipsin levels are significantly elevated in serum, SF, and cartilage in patients with OA.¹⁹⁹ However, the pathway of action between adipsin and OA remains unclear. Adipsin levels have been significantly associated with cartilage volume loss in the lateral compartment of the knee and correlated with the incidence of Total Knee Arthroplasty.^140,200

Fatty Acid Binding Protein 4’s Role in OA

Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP, is involved in lipolysis and is secreted by macrophages and adipocytes.^93,201 In patients with OA, FABP4 levels negatively correlate with cartilage thickness and have been identified as playing a role in cartilage degradation.^202–205 Furthermore, FABP4 has been found to activate the NF-κB signalling pathway via PPARγ, enhancing IL-1β-induced inflammation, oxidative stress, apoptosis, and extracellular matrix degradation in chondrocytes;thus, FABP4 is implicated in promoting chondrocyte degeneration and plays a significant role in the progression of OA.^206,207

Nesfatin-1’s Role in OA

Nesfatin-1, an adipokine, is pivotal in OA development by modulating inflammatory mediators and chondrocytes, though its role in inflammation is debated. This adipokine notably enhances rat chondrocytes’ collagen type II alpha-1 chain (Col2a1) expression and diminishes several inflammatory agents, such as MMPs, cyclooxygenase-2, nitric oxide, prostaglandin E2, and IL-6; additionally, reduces chondrocyte apoptosis, thus safeguarding against OA.^112,208 Conversely, most studies have demonstrated a significant positive correlation between nesfatin-1 levels and OA severity.^209,210 Furthermore, Lee reported that nesfatin-1 contributes to the production of inflammatory cytokines, particularly promoting IL-1β production in osteoarthritic synovial fibroblasts by suppressing miR-204-5p synthesis through the AP-1 and NF-κB pathway.²¹¹ In contrast, some studies suggest that Nesfatin-1, by blocking the activation of the RhoA/ROCK pathway, prevents excessive autophagy in OA cartilage and enhances chondrocyte cytoskeletal integrity.²¹² Thus, Nesfatin-1 is pivotal in OA progression, yet its interactions with inflammatory factors are underexplored, warranting further investigation as a potential therapeutic target for OA.

Serpin Peptidase Inhibitor, Clade E, Member 2’s Role in OA

Serpin peptidase inhibitor, clade E, member 2 (Serpin E2) exhibits beneficial effects on the progression of OA, offering chondroprotective benefits, inhibiting cartilage degradation, and preventing joint destruction in rabbits.^213,214 Crucially, the efficacy of Serpin E2 hinges on its interaction with MMPs.^215,216 Among these, MMP-13 emerges as a critical collagenase involved in cartilage catabolism in OA. Santoro et al demonstrated that Serpin E2 obstructs IL-1-induced MMP-13 expression in chondrocytes via pathways involving ERK, NF-κB, and AP-1, thereby mitigating cartilage catabolism.²¹⁵

Progranulin’s Role in OA

PGRN is an adipokine with multifaceted functions, contributing to chondrogenesis and anti-inflammation in OA and preventing further OA deterioration.^217,218 Atsttrin, a derivative of PGRN, protects against early OA.²¹⁹ Autophagy serves as a protective mechanism for normal cartilage,²²⁰ and its loss is linked to pathological changes in OA.²²¹ PGRN regulates chondrocyte autophagy by modulating the interaction with the ATG5-ATG12 complex, thus providing a protective effect on cartilage.²²² Furthermore, PGRN interacts with the inositol-requiring enzyme 1α, an inositol-requiring enzyme, enhancing the expression of collagen type 2 and maintaining collagen homeostasis to protect cartilage.²²³ As an antagonist of TNF-α signalling, PGRN plays a crucial role in the pathogenesis of inflammatory arthritis in mice, antagonizes TNF-α, and protects against cartilage destruction in OA.^224,225 Additionally, PGRN restores chondrocyte metabolic homeostasis by activating the ERK1/2 signalling pathway and elevating anabolic biomarkers, including collagen type 2 and Aggrecan.²²⁶

Chemerin’s Role in OA

Chemerin exhibits a pro-inflammatory effect, and in vitro studies suggest its role in inflammatory lesions and cartilage degeneration in OA.^17,227,228 This protein is pro-inflammatory in OA; notably, chemerin induces the release of inflammatory mediators such as IL-6, TNF-a, and metalloproteinases from macrophages and chondrocytes.²²⁹ Furthermore, chemerin elevates TLR4 expression and triggers CCL2 release from synovial fibroblasts, enhancing leukocyte migration to inflammation sites and amplifying inflammatory signalling in chondrocytes.¹⁵⁵ Moreover, chemerin intensifies inflammatory signals in macrophages and chondrocytes,²³⁰ influences chondrocyte metabolism by boosting AKT/ERK phosphorylation, and decreases chondrocyte proliferation, worsening OA symptoms.²³¹ Therefore, while chemerin’s role in OA development is acknowledged, its precise pathways and mechanisms warrant further study.

Wnt-1-Induced Signalling Pathway Protein 2’s Role in OA

Emerging adipokines, such as Wnt-1-induced signalling pathway protein 2 (WISP-2) or CCN5, have been linked to OA progression. Found in the chondrocytes and synovial membranes of OA patients, WISP-2 significantly influences OA pathogenesis.^232–234 Studies indicate that WISP-2 counters the effects of IL-1β on MMP-13 and ADAMTS-5, and decreases IL-6 and IL-8 levels in OA chondrocytes through the WNT/β-catenin pathway, thus potentially slowing OA progression.²³⁵

Visceral Adipose Tissue-Derived Serpin’s Role in OA

Visceral adipose tissue-derived Serpin (vaspin), which is expressed at multiple sites and possesses pleiotropic properties, has also emerged.²³⁶ Serum vaspin levels are lower in OA patients than in healthy controls.²³⁷ Vaspin may inhibit the release of pro-inflammatory factors and certain adipokines such as leptin and resistin,²³⁸ influencing the inflammatory process in OA and promoting the development of bone mesenchymal stem cells through activation of the PI3K/AKT pathway.^239,240 Reduced expression of vaspin inhibits cholesterol synthesis via the miR155/LXRα efflux pathway, contributing to the accumulation of cholesterol in the cartilage and the development of OA.²⁴¹

Serum Amyloid A’s Role in OA

Serum Amyloid A (SAA) is a newly discovered adipokine; studies have shown that the level of SAA in serum and synovial fluid (SF) of OA patients was higher than normal, and its expression level was positively correlated with the severity of OA.^242,243 Furthermore, it was found that SAA induces the release of pro-inflammatory cytokines,^244,245 which plays a key role in the inflammatory process of OA and induces the secretion of MMPs by chondrocytes under the control of TGF-b, exacerbating the progression of OA.²⁴⁶

Omentin-1’s Role in OA

Omentin-1 (also known as Intelectin-1) is a newly discovered adipokine, and multiple studies have found that its level is negatively correlated with OA severity.^247,248 Omentin-1 displays anti-inflammatory effects in OA, with both omentin-1 and IL-4 levels significantly reduced in OA patients relative to controls. Studies have shown that omentin-1 triggers IL-4-dependent anti-inflammatory responses and M2 macrophage polarization in OA synovial fibroblasts via PI3K, ERK, and AMPK pathways, thereby preventing cartilage degradation and bone erosion.²⁴⁹ Additionally, omentin-1 has been described as a pleiotropic protective adipokine that offers a repair mechanism for chondrocytes in joint tissue. This is done by attenuating IL-1β-induced G1-phase cell cycle block and inhibiting IL-1-induced cellular senescence, thus protecting chondrocytes from senescence.²⁵⁰

Metrnl’s Role in OA

Metrnl, a newly discovered adipokine, has been linked to the pathogenesis of OA. Studies have shown that higher levels of Metrnl correlate with a reduced likelihood of developing OA.^251–253 It has also been shown that Metrnl can regulate IL-4 and IL-13 expression levels to exert anti-inflammatory effects;Liu has noted that its anti-inflammatory effects are mediated by inhibiting the PI3K/Akt/NF-κB pathway.^254,255

Adipokines as Key Mediators in the Pathogenesis of OA

Adipokines play a pivotal role in the pathogenesis of OA through complex interactions within shared inflammatory and metabolic signaling pathways, including NF-κB, PI3K/Akt, MAPK, and others. These molecules influence critical processes such as chronic inflammation, cartilage metabolism, and bone remodeling, contributing to the progression of OA.

Firstly, Chronic Inflammation Driven by NF-κB and JAK/STAT Pathways: Adipokines such as leptin, resistin, and lipocalin establish a positive feedback loop by co-activating NF-κB and JAK/STAT signaling pathways.^21,113,146 This significantly amplifies the release of pro-inflammatory cytokines (eg, IL-6, TNF-α), maintaining a chronic low-grade inflammatory microenvironment in the joint.^21,113,146 Such sustained inflammation exacerbates cartilage degradation, synovial inflammation, and overall OA progression. Secondly, Cartilage Metabolic Imbalance via PI3K/Akt and MAPK Pathways: Leptin, Visfatin, and Nesfatin-1 also converge on the PI3K/Akt and MAPK pathways to regulate chondrocyte metabolic activity.^{104,112,194,197} This disrupts the balance between cartilage matrix synthesis and degradation, accelerating cartilage degeneration and further driving OA progression.

Thirdly, Bone Remodeling Imbalance via ERK and mTOR Pathways: adipokines such as leptin and osteopontin modulate osteoclast and osteoblast activity through ERK and mTOR signaling pathways.^118,119,177 This results in increased bone resorption, inhibited bone formation, and progressive structural deterioration of bone tissue, destabilizing joint integrity and worsening OA outcomes. Lastly, Insufficient Anti-Inflammatory Protection via PPARγPathways: anti-inflammatory adipokines, including metrnl, and FABP4, exhibit protective effects by mitigating inflammation and preserving joint structures through Wnt/β-catenin and PPARγ pathways.^116,239 However, these protective mechanisms are often insufficient to counteract the strong pro-inflammatory signals driven by other adipokines, limiting their ability to effectively slow OA progression.

Chronic low-grade inflammation and bone destruction, mediated by key adipokines, are fundamental to OA pathogenesis within the framework of MetS. Pro-inflammatory adipokines, including leptin, resistin, and osteopontin, exacerbate cartilage degradation and synovial inflammation by activating signaling pathways such as NF-κB, PI3K/Akt, and WNT/β-catenin, leading to chondrocyte catabolism and inflammatory cascades.^{21,128,183,256} Conversely, protective adipokines like Serpin E2, PGRN, and WISP-2 counteract these processes by suppressing cartilage degradation and enhancing anti-inflammatory mechanisms, promoting tissue homeostasis.^213,215,217 Notably, adipokines such as lipocalin, adipsin, and nesfatin-1 exhibit context-dependent dual roles, either promoting inflammation or supporting cartilage stability, reflecting their complex contributions to OA progression.^112,152,200 Understanding these diverse functional phenotypes and underlying molecular mechanisms is critical for identifying therapeutic targets and advancing treatments for metabolic OA. Epidemiological studies strongly reinforce the link between adipokines and OA, underscoring their pivotal roles in disease initiation and progression. Tables 2 and 3, along with Figure 3, delineate the functional and clinical relevance of various adipokines, illustrating both shared and distinct mechanisms underlying OA pathophysiology. Pro-inflammatory adipokines, such as SAA and chemerin, amplify cytokine cascades, serving as critical markers of OA progression.^217,229 In contrast, anti-inflammatory adipokines like omentin-1 and Metrnl show promise in cartilage repair and symptom alleviation by inhibiting NF-κB signaling and promoting anti-inflammatory pathways.^247,255,

Table 2 The Role of Different Adipokines in the Pathogenesis of OA

Table 3 Adipokines in Osteoarthritis: Multifaceted Roles, Mechanistic Pathways, and Clinical Implications

Figure 3 Pathways of action of multiple adipokines triggering OA.

Conclusion

OA is a complex degenerative joint disease significantly influenced by metabolic dysregulation, with metabolism-related adipokines playing a pivotal role in the pathogenesis of MetS-OA. While previous studies have highlighted the crucial roles of metabolic dysfunction and adipokines in OA progression, the precise mechanisms and interactions remain incompletely understood. The relationship between adipokines and OA is multifaceted, with these molecules exerting varying effects at different stages of the disease, from promoting inflammation and cartilage degradation to potentially modulating repair processes. This complexity underscores the importance of further investigating how adipokines influence OA progression and their roles in both early and advanced stages of the disease.

Future research should focus on elucidating the diverse functions of adipokines at different stages of OA, particularly their dual roles in inflammation, metabolism, and tissue remodeling. A deeper understanding of the complex mechanisms underlying adipokine actions is essential for the development of targeted therapies. Targeting specific adipokines or their receptors could not only alleviate symptoms but also slow disease progression, providing long-term therapeutic benefits for OA patients. Moreover, combining adipokine-targeted treatments with other therapeutic approaches, such as cartilage repair or immune modulation, may offer a more comprehensive and effective disease management strategy.

Abbreviations

OA, Osteoarthritis; MetS, Metabolic syndrome; MetS-OA, Metabolic syndrome-associated osteoarthritis; BMI, Body mass index; IL-6, Interleukin-6; TNFα, Tumour necrosis factor alpha; DM, Diabetes mellitus; PGRN, Progranulin; ROS, reactive oxygen species; HT, Hypertension; DLs, Dyslipidaemias; OP, Osteoporosis ; Nrf-2, nuclear factor erythroid 2-related factor 2; AGEs, advanced glycation end-products; PTOA, post-traumatic osteoarthritis; TMJ-SFs, temporomandibular joint; Ob-Rb, leptin-specific receptor; MMP, metalloproteinase; LCN2, Lipocalin-2; OPN, Osteopontin; MMP13, Metalloproteinase 13; MSCs, Mesenchymal stem cells; FABP4, Fatty acid binding protein 4; Col2a1, Collagen type II alpha-1 chain; Serpin E2, Serpin peptidase inhibitor, clade E, member 2; WISP-2, Wnt-1-induced signalling pathway protein 2; Vaspin, Visceral adipose tissue-derived Serpin; SAA, Serum Amyloid A.

Acknowledgments

The figures in this manuscript were created by Figdraw. We thank Figdraw for providing this professional drawing platform.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was funded by the Shandong Natural Science Foundation (ZR2022MH063 to Wei Li), supported by the National Natural Science Foundation of China (82171521, 82371539 to Chen Li), and received support from the Special Funds of the Taishan Scholars Project of Shandong Province (No. tsqn202211368 to Chen Li).

Disclosure

The authors declare that they have no competing interests.

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