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IL-17 in osteoarthritis: A narrative review

  • Juan Xiao , Ping Zhang , Fang-Lan Cai , Cheng-Gen Luo , Tao Pu , Xiao-Li Pan EMAIL logo and Mei Tian EMAIL logo
Published/Copyright: October 14, 2023
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Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

Osteoarthritis (OA) is a painful joint disease that is common among the middle-aged and elderly populations, with an increasing prevalence. Therapeutic options for OA are limited, and the pathogenic mechanism of OA remains unclear. The roles of cytokines and signaling pathways in the development of OA is a current research hot spot. Interleukin (IL)-17 is a pleiotropic inflammatory cytokine produced mainly by T helper 17 cells that has established roles in host defense, tissue repair, lymphoid tissue metabolism, tumor progression, and pathological processes of immune diseases, and studies in recent years have identified an important role for IL-17 in the progression of OA. This narrative review focuses on the mechanisms by which IL-17 contributes to articular cartilage degeneration and synovial inflammation in OA and discusses how IL-17 and the IL-17 signaling pathway affect the pathological process of OA. Additionally, therapeutic targets that have been proposed in recent years based on IL-17 and its pathway in OA are summarized as well as recent advances in the study of IL-17 pathway inhibitors and the potential challenges of their use for OA treatment.

Keywords: osteoarthritis; interleukin-17; joint cartilage; synovium; target

1 Introduction

Osteoarthritis (OA) is one of the main causes of joint stiffness, pain and disability in the middle-aged and elderly populations, with hip and knee OA ranking 11th on the global list of disabling factors [1]. The pathogenesis of OA is complex, and the etiology is not completely clear. It is currently believed to be the result of a combination of risk factors, mainly including advanced age, obesity, joint misalignment, increased pressure load, genetics, and inflammation, with advancing age and obesity being the most prominent [2]. OA is characterized by progressive cartilage degeneration followed by the gradual development of synovial inflammation, subchondral bone sclerosis, bone redundancy formation, degeneration and tearing of the meniscus, inflammation and fibrosis of the infrapatellar fat pad [3,4], and even involvement of the entire joint [5,6]. Chronic joint pain severely affects the quality of life of OA patients, which can lead to the development of depressive states, increasing the probability of self-harm and suicide [7,8]. With the continued aging of the population and the increase in obesity in recent years globally, the reported number of OA cases increased from 248 million in 1990 to 528 million in 2019, following an increasing trend each year [9]. The current prevalence of OA in China is approximately 15%, and the condition affects up to 50% of people over 60 years of age, with a greater prevalence in women versus men and in rural populations vs urban populations, with geographical variation [10]. This high prevalence results in a huge consumption of medical resources and a huge burden on individuals, the economy, and society [11,12]. However, the current clinical treatments for OA are mainly aimed at relieving pain, protecting joint function, and slowing disease progression, and no non-surgical treatment strategy is available to control or reverse OA [13]. Although, patients with end-stage OA can choose joint replacement surgery, this treatment option is associated with risks of postoperative bleeding, infection, thrombosis, and persistent joint pain, and some patients are unable to tolerate the surgical procedure [14]. Therefore, research to understand the pathogenesis of OA in depth and to identify targets and drugs for effective OA treatment is needed to address urgent clinical problems at present.

OA is the result of an imbalance between cartilage synthesis and degradation that occurs under the combined effects of mechanical and biological factors, such as trauma, inflammation, aging, and various genetic, immune, and metabolic factors [7,15]. Articular cartilage includes chondrocytes and cartilage matrix (mainly containing water, type II collagen, and proteoglycans). Under normal conditions, type II collagen interlinks with other collagens in the extracellcular matrix (ECM) in the form of cross-linked microfibils to maintain the biomechanical skeleton of articular cartilage, and the ECM has a strong water retention capacity (hydrophilic and negatively charged), thus allowing frictionless movement of the articular surfaces and eliminating the crowding forces generated by pressure loads on the articular surfaces [16]. In addition, proteoglycans protect the articular surfaces from compressive deformation by regulating the fluid pressure in the cartilage tissue. With the occurrence of OA, interaction between chondrocytes and ECM is altered, proteoglycans and type II collagen are degraded, chondrocyte catabolism is enhanced, cartilage surfaces are compressed and eroded, and inflammatory factors are increased, leading to synovial inflammation and further aggravating the development of OA [17,18,19].

Chondrocyte differentiation and apoptosis as well as cartilage matrix synthesis and degradation are dynamically balanced to maintain cartilage homeostasis. Disturbance of cytokine homeostasis disrupts this intrachondral homeostasis, and thus, is one of the most important factors in the pathogenesis of OA [20]. Researchers have found elevated levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, and IL-6 in the synovial fluid, synovium, and cartilage ECM of OA patients, which suggests that low-level inflammation is involved in the pathogenesis of OA [21,22,23]. In addition, the infrapatellar fat pad, which is as rich in vascular and neural tissue as the synovium, appears to be an anatomical-functional unit with the synovium, and is thought to be one of the causes of OA joint pain [24,25]. The infrapatellar fat pad also produces pro-inflammatory cytokines and chemokines that induce synovial inflammation and promote OA progression [26]. These cytokines are known to stimulate chondrocytes, disturb the balance of anabolic and catabolic metabolism, induce high expression of matrix metalloproteinase 3 (MMP3), MMP13 and other factors, and contribute to cartilage matrix degradation [27,28]. They also stimulate synovial cells to release proteases, causing synovial inflammation and promoting bone resorption [28], which induces progressive degradation and destruction of articular cartilage. Accordingly, the important roles of cytokines in the pathogenesis of OA have been confirmed.

In recent years, the relationship between the pleiotropic inflammatory cytokine IL-17A (also commonly referred to as IL-17) and OA has attracted considerable attention. Previous studies showed that IL-17 is associated with host defense, tissue repair, lymphoid tissue metabolism, and tumor progression [29], and IL-17 has been most extensively studied in relation to autoimmune diseases, such as rheumatoid arthritis (RA) [30], ankylosing spondylitis [31], and psoriatic arthritis [32]. The circulating IL-17 level was shown to play an important role in the pathogenesis and progression of inflammatory arthritis [33]. Synergy between IL-17 and TNF-α has been demonstrated to activate the production of proinflammatory mediators, such as IL-1β, IL-6, IL-8, prostaglandin E2 (PGE2), and MMPs, to promote the progression of early inflammation to chronic arthritis [34]. In the context of OA, IL-17 affects the inflammatory response, complement production, hypoxia response, angiogenesis, and glycolytic pathways in chondrocytes and synovial fibroblasts [35]. IL-17 may play a crucial role in the pathogenesis of OA and is closely associated with joint pain in OA patients [36]. Significant correlation between IL-17 expression and cartilage defects and bone marrow lesions was observed in the serum of patients with knee osteoarthritis (KOA), and a positive correlation was also observed between IL-17 expression and the severity of KOA [37,38]. Several animal models have also confirmed the role of IL-17 in inflammatory arthritis [39,40,41], and injection of IL-17 into the rabbit knee joint induces a model of OA similar to that induced by the Hulth method [42]. Therefore, This review article summarizes current knowledge regarding the mechanism of action of IL-17 in OA and discusses the potential challenges of using IL-17 inhibitors for the treatment of OA.

2 Introduction of IL-17

The IL-17 family is a class of structurally similar inflammatory molecules that includes six cytokines, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F. They are mainly derived from T helper 17 (Th17) cells, CD8+ T cells, γδT cells, and natural killer (NK) T cells [43] and can also be produced by neutrophils and macrophages during inflammation (Figure 1) [44,45]. The most well-known one is IL-17A (referred to hereafter as IL-17 unless otherwise stated). To achieve their biological effects, members of the IL-17 family must bind to the corresponding receptor (R) complex on the cell surface to regulate gene transcription. The IL-17 recepter (IL-17R) family has five receptor subunit members, which are labeled IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE, of which IL-17A and IL-17F exist as homologs or heterodimers and act together in a complex formed with IL-17RA and IL-17RC. Interestingly, IL-17RA exerts pleiotropic functions by binding and interacting with IL-17RB, IL-17RC, IL-17RD, and IL-17RE [46,47]. In the inflammatory environment, IL-17 can be active against various cells, including keratin-forming cells, fibroblasts, osteoblasts, endothelial cells, and immune cells [48], and is involved in the pathological processes of inflammation, autoimmunity, tumorogenesis, and metabolic disorder through the production of various molecules, such as inflammatory factors (IL-6, IL-1, TNF), chemokines, antimicrobial peptides (AMPs), MMPs, and acute phase proteins (Figure 1) [49].

Figure 1 IL-17 is produced by Th17 cells, CD8+ T cells, γδ T cells, NKT cells, etc. IL-17 acts on keratin-forming cells, fibroblasts, osteoblasts, endothelial cells, and immune cells and participates in the pathological processes of tumor development, immune diseases, and inflammation by inducing production of inflammatory factors, inflammatory mediators, and MMPs.
Figure 1

IL-17 is produced by Th17 cells, CD8+ T cells, γδ T cells, NKT cells, etc. IL-17 acts on keratin-forming cells, fibroblasts, osteoblasts, endothelial cells, and immune cells and participates in the pathological processes of tumor development, immune diseases, and inflammation by inducing production of inflammatory factors, inflammatory mediators, and MMPs.

3 IL-17 signaling pathway

IL-17RA consists of an extra-membrane fibronectin-like structural domain, an intracytoplasmic SEF/IL-17(SEFIR) structural domain and a distal activation structural domain (CBAD). In addition, IL-17RA also has SEFEX, an extension sequence of SEFIR [50]. The signal transduction and negative regulatory pathway of IL-17 consists of four main steps: (1) IL-17 (IL-17A, IL-17A/F, IL-17F) binds to receptor complexes formed by IL-17RA and IL-17RC and induces binding of the receptor SEFIR structural domain to the multifunctional signaling protein Act1 (with E3 ubiquitin ligase activity). Act1 is critical in IL-17 signaling pathway-dependent autoimmune and inflammatory diseases, and IL-17-induced expression of inflammation-related genes is suppressed when Act1 is defective [51]. (2) Act1 rapidly recruits and ubiquitinates TNF receptor-associated factor 6 (TRAF6), a critical step in signaling pathway transduction. TRAF3 and TRAF4 can negatively regulate this pathway by interfering with the coupling between Act1 and TRAF6. Additionally, deubiquitinating enzymes A20 and USP25 can remove the ubiquitination disability of TRAF6 to similarly prevent TRAF6 from binding to Act1. Meanwhile, USP25 also inhibits TRAF5 activity and affects post-transcriptional RNA stability. (3) TRAF6 promotes the activation of mitogen-activated protein kinase (MAPK)/AP-1, C/EBPβ, and δ transcription factor, and through transforming growth factor beta (TGF-β)-activated kinase 1 (TAK1), phosphorylates nuclear factor kappa B (NF-κB), targeting an important transcriptional target NF-κB inhibitor zeta (IBζ), which is involved in psoriasis development. (4) Act1 recruits TRAF2/5 and binds HuR and Arid5a to promote post-transcriptional RNA stabilization (Figure 2) [52,53]. In conclusion, IL-17 signaling is very complex, and the above description summarizes only the main processes. Many specific molecular mechanisms and branches remain to be further explored.

Figure 2 IL-17 signal transduction pathway.
Figure 2

IL-17 signal transduction pathway.

4 Role of IL-17 in the pathogenesis of OA

The etiology of osteoarthritis remains incompletely understood, but various molecular mechanisms have been shown to be involved in this pathological process, including the JAK/STAT signaling pathway [54], PI3K/AKT/mTOR signaling pathway [55,56], p38 MAPK/c-Fos/AP-1 pathway [57], and Wnt/β-linked protein pathway [58]. These signaling pathways have been found to mainly affect the OA pathological process by regulating chondrocyte survival, subchondral bone remodeling, and synovial inflammation. Interestingly, IL-17 is also involved in the degeneration and destruction of articular cartilage and synovial inflammatory processes in the pathology of OA (Figure 3).

Figure 3 Mechanism of action of IL-17 within articular cartilage and synovium in OA. (1) IL-17 reduces autophagy through activation of the PI3K/AKT/mTOR and JAK/STAT3 signaling pathways; (2) IL-17 promotes chondrocyte senescence in OA, and senescent chondrocytes induce differentiation of naive T cells to Th17 cells in a vicious cycle; and (3) IL-17 promotes synovial inflammation.
Figure 3

Mechanism of action of IL-17 within articular cartilage and synovium in OA. (1) IL-17 reduces autophagy through activation of the PI3K/AKT/mTOR and JAK/STAT3 signaling pathways; (2) IL-17 promotes chondrocyte senescence in OA, and senescent chondrocytes induce differentiation of naive T cells to Th17 cells in a vicious cycle; and (3) IL-17 promotes synovial inflammation.

4.1 Cartilage

The degeneration and destruction of articular cartilage are recognized as central to the progression of OA [59] along with the involvement of IL-17 and its pathways, mainly in the form of effects on chondrocyte autophagy, senescence, and cartilage matrix [41].

Autophagy is a stress response mechanism for cell survival that involves removal of intracellular microorganisms through lysosomes and degradation of dysfunctional or damaged organelles and proteins, and is an important system for energy and nutrient metabolic homeostasis within the body [60,61]. Abnormal cellular autophagy can advance the progression of chondrocyte senescence and apoptosis, with peroxide production and mitochondrial dysfunction being the main mechanisms [62]. Previous studies by our group and others have confirmed that autophagy, as a form of cell death, is closely associated with OA progression [63,64].

Furthermore, autophagy and inflammation are two biological processes important for cells in physiological and pathological states, with autophagy regulating innate and adaptive immune responses and, conversely, immune response-induced cytokine release regulating autophagy levels [65,66,67]. IL-17 is known to influence autophagy in two ways. (1) IL-17 promotes autophagy: IL-17 can induce autophagy in B cells in vitro by increasing Erk1/2 phosphorylation, as evidenced by an increase in the activity of autophagy proteins Beclin-1 and P62 on the ubiquitin proteasome system, and by an increase in the anti-apoptotic capacity of B cells [68]. In contrast, 3-MA, an inhibitor of autophagy, significantly reversed the above effects of IL-17. It was found that IL-17 increased the accumulation of RAW264.7 cellular autophagy protein LC3B-II–induced autophagic activity, significantly increased the number and size of cellular autophagosomes, and promoted the antimicrobial activity of primitive macrophages [69]. (2) IL-17 inhibits autophagy expression: In normal skin fibroblasts, IL-17 stimulation significantly increased the expression of p-STAT3 and hypoxia-inducible factor-1α (HIF-1α) and increased P62 activity, suggesting an accumulation of autophagosomes (P62), leading to autophagy defects. hIF-1α inhibitor reversed the IL-17-induced autophagy downregulation [70]. The IL-17/STAT3/HIF-1α/P62 signaling axis cascade is associated with autophagy inhibition.

However, how IL-17 regulates autophagy in OA remains less well characterized. An study observed significantly elevated IL-17 expression in an IL-1β-induced OA chondrocyte inflammation model, which exacerbated autophagy defects and promoted cartilage degeneration by mediating PI3K/AKT/mTOR autophagy-related pathways [41]. In addition, stimulation of mouse osteoblasts with IL-17 was found to suppress the level of autophagy by activating the JAK2/STAT3 signaling pathway and downregulating Beclin 1, LC3, and Atg7 expression [71]. In summary, in OA, IL-17 promotes OA progression mainly by inhibiting autophagy expression, which is closely related to the PI3K/AKT/mTOR and JAK2/STAT3 signaling pathways, and targeting these two pathways and blocking the action of IL-17 may be the direction of OA treatment. Unfortunately, additional research in this specific area is lacking, and it remains unclear whether IL-17 is an independent upstream target of autophagy.

Cellular senescence also is involved in OA pathogenesis [15,72]. Chondrocyte senescence affects articular cartilage biomechanics, biochemistry, and cellular function, making articular cartilage more susceptible to damage [73]. In addition, one of the hallmarks of aging is mitochondrial dysfunction, which in OA leads to an imbalance in cellular energy metabolism and an increase in reactive oxygen species (ROS) production, exacerbating the progression of OA as evidenced by an increase in oxidative stress in articular cartilage, cytokine production, an increase in inflammation-mediated catabolism of cartilage matrix, and increases in calcification of the cartilage matrix and apoptosis of chondrocytes [74,75]. Experiments in an animal model of post-traumatic OA showed anterior cruciate ligament transection (ACLT) induced a Th17-type immune response with increased IL-17 expression and that senescent OA chondrocytes drove the differentiation of naive T cells to Th17 cells [39]. Furthermore, intra-articular injection of neutralizing antibodies to IL-17 into the OA animal model decreased the expression of the senescence marker P16 (Cdkn1α) [39]. Wang et al. reported that stimulation of chondrocytes with IL-17 induces production of reactive oxygen species, monocyte chemoattractant protein-1 (MCP-1), and IL-1β along with increased senescence-associated β-galactosidase activity, a prolonged stationary/gap phase (G0/G1) in the cell cycle, a shortened S-phase in DNA synthesis, and ultimately premature senescence of chondrocytes [76]. In summary, the Th17/IL-17 axis can accelerate chondrocyte senescence, and a reciprocal promoting relationship exists between IL-17 secretion and cellular senescence-associated protein expression. Moreover, this combined effect may induce more rapid destruction of articular cartilage than each single factor.

Chondrocytes are responsible for the synthesis and secretion of cartilage needed to form the cartilage matrix, and this activity is essential for the maintenance of cartilage homeostasis and is regulated by physical and chemical signaling within the joint that influences the physiological function of chondrocytes [77,78]. IL-17 was found to be involved in cartilage matrix synthesis and catabolic pathways [79]. Elevated IL-1β and IL-6 expression was observed in a sodium iodoacetate-induced IL-1 receptor antagonist (IL-1Ra) knockout mouse model of OA, and cartilage tissue thinning and chondrocyte reduction also were observed [80]. However, silencing of IL-17 significantly inhibited inflammatory mediator release and cartilage damage. The same study also stimulated human chondrocytes with IL-17 and found that MMP1, MMP3, and MMP13 were upregulated while SOX9 (a protein associated with chondrocyte anabolism) was downregulated, which led to increased cartilage matrix degradation and exacerbated cartilage tissue damage. Hu et al. reported that treatment of chondrocytes with recombinant IL-17 results in activation of the NF-κB and MAPK signaling pathways, upregulation of the cartilage catabolic factors IL-6, MMP3, and zinc metalloproteinase 4 (ADAMTS-4) expression, promotion of cartilage matrix degradation, disruption of homeostasis within cartilage, and aggravation of OA progression [81]. In summary, stimulation by IL-17 disrupts the balance in cartilage matrix metabolism, and the resulting feedback affects the physiological function of chondrocytes, leading to cartilage tissue degeneration. Thus, the role of IL-17 in OA is not limited to inflammatory effects, as this factor also plays a key role in the pathological progression of OA by influencing chondrocyte senescence, apoptosis, and cartilage matrix degradation.

4.2 Synovium

The synovium is a connective tissue located in the inner layer of the joint capsule that surrounds tendons and forms the lining of bursae and fat pads, which secrete and regulate the formation of synovial fluid, providing nutrients to the chondrocytes [82]. Injury-related molecules, products of mitochondrial dysfunction, cytokines, and metabolites in joints activate synovial cells to promote the release of large amounts of pro-inflammatory cytokines and inflammatory mediators, inducing OA-related cartilage matrix degradation and osteophyte formation [83,84,85]. Pro-inflammatory cytokines and chemokines are central regulators of synovial inflammation in OA [20,21]. Interestingly, IL-17 amplifies the synovial inflammatory effects in OA by promoting the expression of pro-inflammatory factors (e.g., IL-6 and IL-1β) and chemokines (e.g., CXCL8, CCL20, CXCL3, and CXCR4) [86]. Deligne et al. found that IL-17 and IL-22 are highly expressed in conditioned medium collected from synovial tissues of OA patients and responsible for inducing the combined release of IL-6, IL-23 and TGF-β1; upregulating MMP9 expression; and ultimately driving synovial inflammation and cartilage matrix degradation [87]. Moreover, in a clinical trial of end-stage hip and knee OA, patients with detectable IL-17 levels in synovial fluid had significantly increased levels of adipokines (leptin, resistin), IL-6, C-C motif chemokine ligand 2 (CCL2), CCL17, and nerve growth factor (NGF) [88]. These findings supported those of previous studies regarding the involvement of adipokines in cartilage degeneration, synovitis, subpatellar fat pad changes, and bone formation [89,90]. Again, IL-17 was shown to promote OA progression by increasing adipokine and inflammatory factor production. In conclusion, IL-17 itself has limited pro-inflammatory effects and cannot directly act on chondrocytes, but it exerts intense inflammatory effects by enhancing and synergizing the pro-inflammatory effects of other cytokines and inflammatory mediators, leading to cartilage degradation, matrix degradation, and synovial inflammation in OA.

5 IL-17–based therapeutic targets and drugs for OA

5.1 Targets

Levels of long non-coding (lnc)RNA cancer susceptibility candidate 2 (lncRNA CASC2) were found to be elevated in the blood and synovial fluid of OA patients, and lncRNA CASC2 was shown to regulate chondrocyte proliferation and apoptosis through mediation of the IL-17 signaling pathway [91]. In human OA synovial fibroblasts (OASFs), the CCN family protein connective tissue growth factor (CCN2) inhibits miR-655 synthesis by mediating the ILK and Syk signaling pathways, whereas miR-655 can bind to IL-17 and directly inhibits IL-17 activity; therefore, CCN2 down-regulates miR-655 expression and indirectly promotes IL-17 synthesis, leading to increased inflammation in OA [40]. Low levels of lncRNA growth arrest-specific transcript-5 (GAS-5) were shown to affect IL-17–related immune and cytokine expression and to be a potential marker of OA progression [92]. The cyclic RNA ciRS-7/micro-RNA7 (mi-RNA7) axis is aberrantly expressed in OA and may drive OA progression through upregulation of IL-17–mediated inflammatory responses [43]. IL-17 is the target gene of miR-136, the expression of which is negatively correlated with miR-136 expression, and thus, miR-136 can be used as a potential biomarker of KOA [93]. TRAF3 significantly inhibits IL-17–induced activation of NF-κB and MAPK, as well as the production of downstream MMPs, resulting in a protective effect against OA [49]. miR-34a, miR-146a, and miR-181a are mediators of adipokine-induced oxidative stress and synovial inflammation in humans with OA via NF-κB pathway expresssion in synoviocytes [94]. In conclusion, most therapeutic targets for OA based on IL-17 and its signaling pathway are related to mRNA expression, and targeting of the gene transcription–translation pathway is expected to be a new strategy for OA therapy.

5.2 Drugs

According to the 2019 edition of the Chinese Osteoarthritis Diagnosis and Treatment Guidelines, OA is most commonly treated currently with a combination of treatments, including health education, weight management, symptomatic drug therapy (non-steroidal anti-inflammatory drugs, NSAIDs), intra-articular sodium hyaluronate injection, physical therapy, and surgery, with the aims of relieving pain and improving joint function [13,95,96,97]. The 2019 American College of Rheumatology/Arthritis Foundation guidelines on OA of the hands, hips, and knees emphasize exercise, weight loss, self-management (tai chi), use of canes and hand orthotics and braces, oral and topical NSAIDs, intra-articular glucocorticosteroid injections, acupuncture, and heat treatments, to name a few, but none of them can cure OA [97]. These guidelines are similar to the Chinese guidelines for the diagnosis and treatment of osteoarthritis. However, NSAIDs can cause gastrointestinal, hepatic, renal, and cardiovascular side effects, and thus, their use should be limited [98]. Several new therapeutic approaches have been explored in recent years, including combination injections of nerve growth factor, stem cells, and platelet-rich plasma, but the balance of efficacy and safety for these approaches remains questionable [5,99]. Accordingly, treatment of OA remains a challenge worldwide. Multiple studies in recent years have demonstrated that regulation of Th17 cells, IL-17 expression, IL-17 signaling pathway activation, and mRNA expression of inflammatory mediators may be effective strategies for treating OA, with effects of reducing cartilage tissue damage and improving joint pain, inflammation, and function (Table 1). The most important of these effects is the control of synovial inflammation in OA.

Table 1

Potential IL-17–related treatments for OA

Drug name Target Research platform Effect Refs.
RA10-6 IL-17/IL-6 Mice Suppression of OA synovial inflammation [110]
Krocina™ Th17/IL-17 Humans (clinical trial) Suppression of OA synovial inflammation [111]
Resveratrol IL-17/NF-κB Rats Repair of OA soft tissue damage [111]
Platelet-rich- plasma IL-17 Rats Improvement of joint function, pain and inflammatory [112,113,114]
Baccharis IL-17 Mice Suppression of OA immune inflammatory [115]
Pioglitazone IL-17/NF-κB Human myeloid cells and tissues Inhibition of mRNA expression of inflammatory mediators [116]
1,25-Vit D3 Th17 Dendritic cells Inhibition of pro-inflammatory cytokine [117]
Dexamethas-one Th17 Dendritic cells Inhibition of pro-inflammatory cytokine [118]
Apremilast IL-17 ATDC5 chondrocytes Inhibition of inflammatory factors, cellular senescence, ROS [76]
Salidroside CD4+/IL-17 Rats Regulates inflammation and immune response [118]

6 Inhibitors of IL-17

Inhibitors of IL-17 or the IL-17 signaling pathway, including Secukinumab (AIN457), Ixekizumab (LY2439821), and Brodalumab (AMG827), have been approved in recent years for clinical use for the treatment of ankylosing spondylitis [100,101], moderate-to-severe plaque psoriasis and psoriatic arthritis [102,103,104], radiographic and nonradiographic spondyloarthritis [105], and Netherton’s syndrome [106] (Table 2), and have shown excellent efficacy, safety, and tolerability. Additionally, some small molecule inhibitors of the orally available IL-17 pathway continue to be studied in the clinical research phase, such as IMU-935, an inhibitor of retinoic acid-related orphan receptor γt (RORγt), which is a major regulator of Th17 cell secretion and IL-17A/F production in innate and adaptive immunity and is involved in the regulation of bacterial and fungal immune responses [107]. As a treatment for psoriasis, IMU-935 was shown to reduce the release of pro-inflammatory cytokines and inflammatory mediators by inhibiting the RORγt/Th17/IL-17 signaling pathway [108,109], but its drug efficacy and risk of adverse events have yet to be established. Although IL-17 pathway inhibitors are not currently used for the treatment of OA, research evidence that IL-17 plays an important role in the pathological progression of OA and is positively correlated with OA severity suggests that inhibitors of IL-17 and its pathway may become the next clinical research target for OA treatment strategies.

Table 2

Mechanism and characteristics of drugs that inhibit IL-17 or the IL-17 signaling pathway

Drug Target Molecular mechanism Refs.
Secukinumab IL-17A Human recombinant monoclonal antibody of IgG1/κ isotype; selectively binds to IL-17A and inhibits its combination with IL-17RA; blocks trans- duction of IL-17 signaling pathway. [119,120]
Ixekizumab IL-17A Human IgG4/κ monoclonal antibody; binds to IL-17A with high affinity and selectivity to neutralize its activity; inhibits release of proinflamma- tory cytokines and chemokines. [121]
Brodalumab IL-17RA Human monoclonal antibody of IgG2/κ isotype; specifically blocks IL-17R and inhibits proinflammatory signaling inducted by multiple IL-17 cytokines, including IL-17A and IL-17F. [122]
IMU-935 RORγt Specifically inhibits the RORγt/Th17/IL-17 signaling pathway; affects Th17 cell secretion and IL-17A/F production; inhibits release of relat-ed pro-inflammatory cytokines and inflammatory mediators. [108,109]

Although down regulation of IL-17 and inhibition of the IL-17 signaling pathway can be beneficial in OA as mentioned above, inhibitors of IL-17 and its pathway are currently inappropriate for the treatment of OA based on the mechanism of action of IL-17 in the pathological process of OA, and many potential challenges persist. (1) IL-17 cannot act directly on chondrocytes but rather affects chondrocyte survival by indirectly upregulating or downregulating the expression of related pathways and proteins. Inhibiting IL-17 expression can reduce its role in promoting chondrocyte apoptosis and senescence but cannot block the pathological changes that occur in OA itself. (2) The pro-inflammatory effect of IL-17 itself is limited; this effect is instead, mainly achieved by synergizing and amplifying the effects of other pro-inflammatory factors and inflammatory mediators to indirectly promote synovial inflammation in OA. Thus, inhibiting the activity of IL-17 and its receptors only weakens or eliminates this amplifying effect but cannot block the occurrence of synovial inflammation. (3) OA progression is supported by many molecular mechanisms that are connected by subtle links. It is not accurate to consider IL-17 activity as an independent cause of OA. Therefore, an in-depth understanding of the relationship between IL-17 and other signaling pathways in OA is critical. Much basic and clinical research is needed to address questions like whether targeting IL-17 gene expression and inhibiting IL-17 pathway activation will have different effects, and whether the combined application of IL-17 inhibitors and blockers of other pathways will have different efficacies.

7 Conclusions

IL-17 is involved in the maintenance of innate and adaptive immunity, and dysregulated production of IL-17 has been shown to promote OA development from multiple perspectives. On the one hand, it promotes OA progression by regulating chondrocyte autophagy and senescence and cartilage matrix degradation, while on the other hand, it induces synovial inflammation by mediating the IL-17 signaling pathway to promote the release of inflammatory cytokines and adipocytokines. These research findings provide valuable evidence for the application of inhibitors of IL-17 and its signaling pathway in OA treatment. Additionally, IL-17 expression was found to be positively correlated with the severity of OA, and thus, it may become a new immunological indicator for evaluating the efficacy of OA treatment and may be an effective target for OA therapy. However, the following questions persist regarding the role of IL-17 in OA: (1) Does IL-17 affect chondrocyte mitosis and cell cycle progression in OA? (2) Are multiple members of the IL-17 family involved in OA development? (3) What relationships exist between IL-17 and other signaling pathways, and what are their side effects? In the future, it will be important to also investigate the impact of IL-17 on other joint tissues such as the meniscus and infrapatellar fat pad, considering that OA is a whole joint disease. A clear understanding of the specific molecular mechanism of IL-17’s action in OA and a means to target this axis accurately without affecting physiological functions could facilitate effective approaches for the prevention and treatment of OA based on IL-17 and its signaling pathways.

  1. Funding information: This work was supported by the Foundation of Guizhou Science and Technology Department (No. QIANKEHEZHICHEN [2023] YIBAN576) and the Foundation of Zunyi Science and Technology Department (Serial Number. HZ359(2022)).

  2. Author contributions: M.T. designed the framework of the manuscript. J.X., P.Z. and X.P. wrote the manuscript and participated in the revision. F.C., C.L., T.P. checked the related literature. All authors reviewed the final version and agreed to its submission. All authors have read and agreed to the published version of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Received: 2023-04-26
Revised: 2023-08-18
Accepted: 2023-09-07
Published Online: 2023-10-14

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0747
Keywords for this article
osteoarthritis; interleukin-17; joint cartilage; synovium; target
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers
  3. Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
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  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
  15. Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1
  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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