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Review Article
Osteoarthritis is a degenerative joint disease driven partly by IL-1β-mediated inflammation. IL-1β promotes cartilage degradation through NF-κB, MAPK, and Wnt pathways. Although anti-IL-1 therapies demonstrate strong preclinical chondroprotective effects, clinical efficacy remains inconsistent due to heterogeneity in osteoarthritis and complex cytokine interactions, limiting therapeutic efficacy of single-target therapeutic strategies.
Osteoarthritis (OA) is a prevalent degenerative joint disease and a leading cause of chronic pain and disability in the aging global population. Its pathogenesis is characterized by progressive articular cartilage degeneration, concomitant synovial inflammation, and aberrant subchondral bone remodeling. While the precise etiology is multifactorial and not fully elucidated, chronic, low-grade inflammation is recognized as a critical driver of disease progression. This inflammatory milieu disrupts the homeostatic balance between anabolic and catabolic processes in joint tissue. A complex network of cytokines and chemokines sustains this pathological state, with interleukin-1 (IL-1) emerging as a pivotal mediator. IL-1, particularly IL-1β, exerts potent catabolic effects by promoting the expression of matrix-degrading enzymes (e.g., MMPs, ADAMTS) while simultaneously suppressing the synthesis of essential extracellular matrix components, such as type II collagen and aggrecan. This dual action accelerates cartilage breakdown and undermines its repair capacity, identifying IL-1 signaling as a promising but clinically limited therapeutic target. This review details the central role of IL-1 in OA pathophysiology and dissects its key downstream signaling pathways, including NF-κB and MAPK activation. Furthermore, it provides a comprehensive summary and critical appraisal of current and emerging therapeutic strategies targeting the IL-1 pathway, evaluating their potential to modify disease progression and alleviate symptoms.
Osteoarthritis (OA) is a common degenerative joint disease among middle-aged and elderly individuals worldwide, and it is a leading cause of disability, imposing a significant burden on both individuals and society. OA is characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone remodeling1. An increasing body of evidence suggests that OA is associated with various risk factors, including demographic characteristics, genetic susceptibility, age, obesity, diet, and personal immune factors. It is also significantly related to abnormal joint stress and injury2,3,4,5,6. Current treatment strategies for OA primarily involve pharmacological and physical therapies aimed at alleviating pain and stiffness and preserving functional mobility. However, mainstream clinical treatments, including NSAIDs and physical therapy, merely alleviate clinical symptoms rather than reverse irreversible articular cartilage pathological damage, and no mature disease-modifying osteoarthritis drugs (DMOADs) have been approved for widespread clinical application6,7. As a result, the ultimate outcome for many severe patients remains joint replacement surgery1,8,9.
Previous studies have suggested that abnormal mechanical stress is the most significant risk factor leading to cartilage destruction10. Abnormal mechanical load induces micro-damage of chondrocytes and further activates the IL-1β-mediated inflammatory cascade, forming a bidirectional regulatory loop between mechanical injury and inflammation in OA11,12. Recent studies have shown that inflammatory factors play a crucial role in the pathological changes of OA, being closely associated with the progressive destruction of the synovium and cartilage4,13,14,15. Chondrocytes, when subjected to abnormal stimuli, secrete large amounts of inflammatory factors, such as IL-1 and tumor necrosis factor-alpha (TNF-α), which, in turn, stimulate the secretion of hydrolytic enzymes, including matrix metalloproteinases (MMPs). MMPs possess a specific ability to degrade type II collagen, leading to cartilage destruction and disrupting the balance between anabolic and catabolic processes in chondrocytes16,17. In the early stages of OA, cartilage actively attempts self-repair; however, inflammatory factors can alter the normal function of the synovium, cartilage, and subchondral bone, significantly impairing their reparative capacity. This ultimately results in reduced extracellular matrix components and water content in the cartilage, causing structural changes in the joint, such as narrowing of the joint space, subchondral bone sclerosis, and the formation of bone spurs. Clinically, this is manifested as pain, deformity, and significant limitation of movement18.
Despite numerous studies, the exact etiology and pathogenesis of OA remain unclear. It is widely believed that inflammatory cytokines and their associated signaling pathways play a crucial role in the development and progression of OA19,20,21. The most important inflammatory cytokines include IL-1, TNF-α, and IL-622, and other minor cytokines, including IL-15, IL-17, IL-18, and IL-21, also participate in disease progression as secondary inflammatory mediators23,24, with IL-1 being widely studied in both in vitro and in vivo OA models. IL-1β is characterized by strong catabolic activity and the capacity to amplify a cascade25. It initiates synovial inflammation and cartilage degradation at the early OA stage and acts as an upstream regulator, triggering the release of various secondary inflammatory mediators, making IL-1 the most representative and research-worthy inflammatory mediator for OA mechanistic exploration and therapeutic development26,27. This review discusses the role of pro-inflammatory cytokines in the pathophysiology of OA, with a particular focus on the IL-1 family. Additionally, it explores the major inflammatory signaling pathways and the current progress in anti-IL-1 therapies for OA, providing new insights into OA mechanisms and potential treatments.
The literature retrieval for this review was conducted in the PubMed, Web of Science, and Embase databases, using the following search terms: "Osteoarthritis", "Interleukin-1", "Chondrocyte", "Inflammatory signaling pathway", and "Anti-IL-1 therapy". English original articles, systematic reviews, and randomized controlled trials (RCTs) focusing on IL-1-mediated OA mechanisms and targeted therapy were included, while case reports, conference abstracts, and non-English literature were excluded. A total of 155 articles were initially retrieved, and 134 valid references were finally screened after deduplication and quality evaluation.
Existing comprehensive reviews regarding IL-1 in OA mainly focused on classical signaling pathways and traditional therapeutic agents27,28. This review fills the existing knowledge gaps by: (1) summarizing negative clinical trial results of anti-IL-1 drugs published from 2023 to 2025; (2) supplementing the upstream regulatory mechanism of NLRP3 inflammasome and chondrocyte pyroptosis; (3) proposing biomarker-guided stratified personalized treatment strategies; (4) updating the latest research progress of gene therapy and biomaterial delivery systems.
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The role of IL-1 in the progression of OA
IL-1 and its close association with the onset of OA
Extensive in vitro studies have demonstrated that IL-1 induces pathological changes similar to those seen in OA cartilage29. In vivo studies have clearly shown the negative effects of IL-1 following intra-articular injection, and in OA animal models, IL-1 antagonists effectively slow the degenerative changes in the cartilage matrix30. Clinically, the enrolled OA patients are divided into Patients with non-traumatic knee OA (mean age 60 years) and patients with post-traumatic knee OA (mean age 56 years)31. Clinical studies indicate that elevated IL-1β expression in peripheral blood leukocytes (PBL) of OA patients is associated with increased pain, functional decline, and a higher risk of radiographic progression of OA32,33,34. Whether in vivo or in vitro, it is evident that IL-1β expression levels are positively correlated with OA pathological severity and clinical pain35. The important biological functions of IL-1 in OA are primarily mediated through two key molecular pathways9 (Figure 1).
IL-1 family factors and receptors
The IL-1 family comprises IL-1α, IL-1β, IL-36, IL-37, IL-38, and IL-1 receptor antagonist (IL-1Ra). Distinct biological properties exist between IL-1α and IL-1β: IL-1α is expressed stably and released upon chondrocyte death, while mature IL-1β gains bioactivity only after inflammasome-mediated cleavage36. As a key pro-inflammatory mediator37. IL-1β binds to the membrane IL-1RI to trigger downstream signals. This receptor is widely expressed in normal knee tissues and is markedly upregulated in OA chondrocytes and synovial fibroblasts38,39. Given that IL-1 family cytokines can induce strong inflammatory responses, the presence of cytokine antagonists and decoy receptors is crucial for inhibiting IL-1 family signal transduction40. IL-1RII binds IL-1β without initiating intracellular signals to curb inflammatory reactions41. Endogenous IL-1Ra secreted by joint cells also exerts potent anti-inflammatory effects42. Plasma IL-1Ra levels correlate with radiographic damage in symptomatic knee OA43, reflecting a dynamic balance between pro-inflammatory and anti-inflammatory mediators throughout disease progression.
IL-1 and cartilage synthesis and catabolic metabolism
IL-1β and TNF suppress chondrocyte anabolic activity, downregulating essential extracellular matrix (ECM) components such as type II collagen (Col-II) and aggrecan44,45,46,47. Conversely, these cytokines promote a catabolic shift by stimulating chondrocytes to secrete key proteolytic enzymes, including MMP-1, MMP-3, and MMP-1348,49, and ADAMTS-450,51. This dysregulated expression is conserved across species and observed in human OA synovium. In a porcine knee OA model, elevated IL-1 levels increased MMP and nitric oxide (NO) production, accelerating the degradation of Col-II and proteoglycans in cartilage and meniscus, which correlated with reduced tissue mechanics and radiographic disease progression52.
Collectively, in vivo and in vitro evidence confirms that IL-1β and TNF disrupt chondrocyte metabolic homeostasis by enhancing catabolic enzyme release while inhibiting matrix synthesis, driving ECM destruction and remodeling1. These findings establish IL-1 and TNF signaling as pivotal drivers of cartilage degeneration in OA, underscoring the therapeutic potential of targeting these pathways.
IL-1 and pro-inflammatory cytokines and chemokines
Inflammatory mediator imbalance dominates OA pathogenesis. IL-1β, TNF-α, and IL-6 trigger signaling cascades to upregulate catabolic enzymes and chemokines, recruiting inflammatory cells and aggravating joint injury22. Secreted by chondrocytes, monocytes, and synovial cells, IL-1β and TNF surge in lesional tissues and dominate cartilage destruction and inflammatory progression19. IL-1β exerts dual effects on cartilage homeostasis53. This contradictory phenomenon is mainly observed in the C57BL/6 mouse medial meniscus destabilization (DMM) model. Low physiological levels sustain chondrocyte autophagy and antioxidation, yet excessive IL-1β triggers inflammatory degeneration. Full suppression of IL-1 may break immune stability, which accounts for the limited clinical outcomes of high-dose single anti-IL-1 therapy54.
A vicious cycle exists in OA: cartilage degradation products amplify pro-inflammatory cytokine expression, which, in turn, accelerates the degeneration of joint structures55. IL-1β and TNF induce chemokines (e.g., IL-856, MCP-1/CCL257, CCL5/RANTES58, MIP-1a19) and other cytokines (e.g., IL-6, IL-17, IL-1859,60), further promoting catabolism. These cytokines also upregulate inflammatory mediators like PGE2, NO, cyclooxygenase-2 enzyme (COX-2), and soluble phospholipase A219,59. NO and PGE2 facilitate ECM degradation by activating MMP13 and ADAMTS-5, inhibiting the anti-inflammatory IL-1Ra, and promoting chondrocyte apoptosis9,19,61. Additionally, IL-1β and TNF stimulate reactive oxygen species (ROS) production62 while downregulating antioxidant enzymes (e.g., superoxide dismutase, catalase)63, thereby augmenting oxidative damage to cartilage. DAMPs released by damaged chondrocytes can activate TLR4, further upregulating IL-1β expression64. Collectively, IL-1β and TNF negatively regulate cartilage through multifaceted pathways involving inflammatory factors, chemokines, mediators, and oxidative stress.
NLRP3 inflammasome-mediated IL-1β maturation and chondrocyte pyroptosis
The NLRP3 (NOD-like receptor thermal protein domain-associated protein 3) inflammasome is the canonical upstream molecular complex mediating mature IL-1β production65. Under an OA inflammatory microenvironment, damage-associated molecular patterns (DAMPs) trigger NLRP3 inflammasome assembly, which activates caspase-1. Activated caspase-1 cleaves inactive pro-IL-1β into biologically mature IL-1β, and simultaneously cuts GSDMD to form cell membrane pores, inducing chondrocyte pyroptosis. Pyroptosis further releases intracellular inflammatory factors, forming an irreversible inflammatory vicious cycle in joints66. Furthermore, aging chondrocytes exhibit senescence-associated secretory phenotype (SASP), continuously secreting high levels of IL-1β and sustaining chronic low-grade inflammation in elderly OA patients67.
Key signaling pathways of IL-1 in the progression of OA
IL-1β and TNF mediate pro-inflammatory and catabolic effects by binding to their receptors and activating multiple signaling pathways, collectively accelerating OA progression. The main signaling pathways involved include the mitogen-activated protein kinase (MAPK) pathway, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, and the wingless-type MMTV integration site family (WNT) pathway68,69.
MAPK signaling pathway
IL-1β induces catabolic processes through the MAPK signaling pathway, leading to the degradation of the cartilage matrix. The MAPK family includes extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. These kinases regulate cell proliferation, differentiation, stress responses, and metabolic processes through different mechanisms (Figure 2).
ERK signaling pathway
Studies have shown that IL-1β activates the MAPK/ERK1 pathway, promoting the phosphorylation and activation of ERK via the intracellular Ras-Raf-MEK-ERK signaling cascade. Once activated, ERK further regulates the expression of transcription factors, such as activator protein 1 (AP-1) and c-Fos, which, in turn, enhance MMP expression. This leads to upregulation of MMP3 and MMP13 expression, inhibition of Col-II and aggrecan expression, and suppression of chondrocyte proliferation70,71. In addition to inducing catabolic processes in articular cartilage, IL-1β also stimulates the secretion of inflammatory factors such as LIF and IL-6, further amplifying the catabolic effects of IL-1β72.
Studies have shown that silencing ERK1 or ERK2 alone can suppress IL-1β-mediated increases in COX-2 and PGE2 production, whereas combined knockdown exhibits a synergistic effect. This suggests that ERK1 or ERK2 may be potential therapeutic targets for the inflammatory response in OA. Additionally, the ERK pathway can also be activated by PGE2, NO, and COX-2, providing a positive feedback mechanism that upregulates the effects of IL-1β itself73.
p38 MAPK signaling pathway
IL-1β can also activate a series of transcription factors through the p38 MAPK pathway. Activation of the p38 MAPK pathway directly promotes the expression of MMPs, including MMP3 and MMP13, which degrade ECM components such as collagen and proteoglycans. Similar to the effects of the ERK pathway, these effects can be reversed by p38-specific inhibitors72,74,75. The p38 MAPK pathway can activate the MKK3, p38α-MAPK, and runt-related transcription factor 2 (RUNX2) pathways, which are responsible for promoting hypertrophic differentiation and upregulation of catabolic enzymes76. Additionally, it can induce increased expression of COX-2 and PGE277. Moreover, the p38 pathway is involved in the upregulation of glucose transporter proteins GLUT1 and GLUT6, enhancing glucose transport and thereby affecting chondrocyte metabolic processes78. IL-1β can directly induce the expression of apoptotic genes through activation of the p38 MAPK signaling, mediating chondrocyte apoptosis79, or it can occur through activation of the p38 pathway via PDK1-mediated signaling80, further exacerbating cartilage degeneration.
JNK signaling pathway
IL-1β induces chondrocyte dedifferentiation by activating JNK and activator protein 1 (AP-1) and downregulates the expression of Col-II by inhibiting SOX-9 gene expression81. Upon activation of the JNK signaling pathway, ADAMTS-4 expression is increased82. In contrast to ERK and p38, JNK-2 activation induces the upregulation of the major aggrecanase ADAMTS-5 in human cartilage and mediates aggrecan degradation through the tumor necrosis factor receptor-associated factor 6 (TRAF-6)/transforming growth factor-β-activated kinase 1 (TAK-1)/MKK-4/JNK-2 pathway83. JNK signaling activation also enhances the catabolic effects of pro-inflammatory cytokines, such as IL-6, via ERK and p38 pathways in chondrocytes75. Furthermore, IL-1β induces the production of vascular endothelial growth factor (VEGF) in chondrocytes via the JNK signaling pathway, thereby upregulating the expression of MMP1 and MMP384. Additionally, phosphorylated JNK signaling plays a crucial regulatory role in chondrocyte apoptosis85.
Overall, IL-1β activates ERK, JNK, and p38 MAPK via the MAPK signaling pathway, thereby enhancing the expression of catabolic enzymes in chondrocytes and promoting the degradation of collagen and proteoglycans in the cartilage matrix. This process not only disrupts the structural integrity of cartilage but also drives further cartilage degeneration and the loss of cartilage tissue function22,26.
NF-κB signaling pathway
IL-1 plays a critical role in the onset and progression of OA by regulating the NF-κB signaling pathway. The binding of IL-1β to IL-1RI promotes the activation of the MyD88-dependent signaling pathway. IRAKs play a central role in this complex, where IRAK1 and IRAK4 phosphorylate and activate TRAF6 (TNF receptor-associated factor 6). TRAF6, in conjunction with other signaling molecules, activates the IKK (IκB kinase) complex. Upon activation of IKK, IκB proteins (NF-κB inhibitors) are phosphorylated and degraded. The degradation of IκB releases NF-κB, allowing it to translocate into the nucleus. Once in the nucleus, NF-κB binds to specific DNA sequences, promoting the expression of inflammatory cytokines and MMPs. These actions degrade the cartilage matrix, induce chondrocyte apoptosis, further reduce chondrocyte numbers and function, impair cartilage repair capacity, and ultimately exacerbate cartilage degenerative changes.
IL-1β-induced activation of the NF-κB signaling pathway can downregulate the expression of the SOX9 gene, thereby inhibiting the synthesis of Col-II86. However, NF-κB signaling may not be directly associated with aggrecan degradation83. NF-κB signaling activation also promotes the expression and release of MMPs, such as MMP1 and MMP13, and aggrecanases87,88,89,90. Additionally, IL-1β stimulates the production and release of various chemokines via the NF-κB pathway, recruiting additional inflammatory cells into joint tissue, further promoting IL-1β secretion and increasing the complexity of the inflammatory vicious cycle in OA (Figure 2).
In addition, IL-1β targets AP-1 via the PI3K/AKT/IKKα pathway to induce the synthesis and secretion of pro-inflammatory cytokines such as IL-6 and TNF-α22,91. It can also activate the PI3K/AKT/NF-κB pathway to induce the production of inflammatory mediators, including ROS, COX-2, iNOS, PGE2, and NO89,92,93. Studies have shown that adenovirus-mediated NF-κBp65-specific siRNA [Ad-siRNA (NF-κBp65)] significantly downregulates NF-κB activation and NF-κBp65 expression in knee joint cartilage, notably inhibiting the pro-inflammatory effects of IL-1β and delaying the disease progression in a rat OA model94.
Wnt signaling pathway
Wnt/β-catenin signaling is one of the major contributors to the pathology of OA95, playing a crucial role in the imbalance between anabolic and catabolic processes in chondrocytes and serving as an important therapeutic target in current research96. During cartilage degeneration, IL-1β activates the Wnt/β-catenin signaling pathway, promoting the abnormal proliferation of osteoblasts and chondrocytes and exacerbating cartilage matrix degradation. Activation of the Wnt/β-catenin pathway may also stimulate IL-1β secretion, creating a positive feedback loop that further intensifies local inflammation. Recent studies have shown that IL-1β upregulates the expression of inducible NO synthase (iNOS) in chondrocytes, promoting the release of NO, which in turn activates the Wnt signaling pathway, stimulating the expression and release of MMPs and ADAMTS proteases in chondrocytes97,98. This process enhances the matrix degradation induced by IL-1β. In OA mouse models and human OA cartilage, Wnt-induced signal protein 1 (WISP-1) expression is upregulated, stimulating macrophages and chondrocytes to secrete various MMPs and aggrecanases, leading to the destruction of joint cartilage matrix99. This may contribute to the mechanisms underlying age-related remodeling and degradation of articular cartilage matrix.
IL-1β indirectly regulates Wnt signaling by activating inflammatory pathways such as NF-κB and MAPK. Studies have shown that IL-1β can upregulate the expression of Wnt-5A and induce the expression of multiple MMP genes via the JNK pathway, while inhibiting the expression of Col-II100. Interestingly, Wnt-11 exhibits opposite effects after IL-1β stimulation and upregulates Col-II expression levels through the protein kinase C (PKC) pathway101. The levels of Wnt signaling antagonists, such as Frizzled-related protein (FRP) and Dkk-1, are associated with the progression of hip osteoarthritis (RHOA) in elderly women102. Higher levels of FRP can reduce the risk of RHOA, while increased serum levels of Dkk-1 are linked to the slowing of RHOA progression. These findings suggest that the Wnt signaling pathway may not merely exert simple catabolic activity but also involve more complex regulatory roles in OA progression (Figure 2).
Comprehensive summary of IL-1-related signaling pathways
Three core signaling pathways (MAPK, NF-κB, and Wnt) exhibit significant crosstalk in IL-1-mediated OA progression. The MAPK family mainly regulates the secretion of catabolic enzymes and chondrocyte dedifferentiation; NF-κB acts as a central inflammatory transcription factor to amplify the inflammatory cascade; the Wnt pathway drives abnormal bone remodeling and cartilage hypertrophy. These three pathways jointly promote joint degeneration, and no single pathway works independently103.
Current status of anti-IL-1 therapy in OA
Current in vitro cell studies and OA animal model research suggest that blocking IL-1 and TNF signaling pathways may delay cartilage degradation in OA and have potential clinical implications. In clinical research, anti-cytokine therapy for OA has made notable progress. IL-1 is a critical therapeutic target in OA treatment. The strategies targeting IL-1 primarily include the following approaches: IL-1 inhibitors exert their anti-inflammatory effects by inhibiting the synthesis and biological activity of IL-18,104; IL-1Ra are anti-inflammatory proteins that bind to the IL-1 receptor and block its activity, while IL-1 antibodies are immunoglobulins that have the ability to neutralize IL-1α and/or IL-1β isoforms (Figure 3).
IL-1 inhibitors
Symptomatic Slow-Acting Drugs for Osteoarthritis (SYSADOA) are primarily used for the non-acute treatment of OA, including Diacerein105, glucosamine, and chondroitin sulfate (CS). SYSADOA is recommended for long-term OA treatment, either alone or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), with Diacerein having the most clinical research106,107. Diacerein, an anthraquinone derivative, is also referred to as a disease-modifying OA drug (DMOAD) or a cartilage protector. Its main mechanism of action is the inhibition of IL-1β production and the activation of related signaling pathways, thereby exerting anti-catabolic effects108. The routine oral administration regimen of diacerein is 50 mg twice daily, with a continuous treatment cycle of 24 weeks109.
Research has shown that Diacerein is effective for patients with knee and hip OA, providing pain relief and functional improvement comparable to that of nonsteroidal anti-inflammatory drugs (NSAIDs) such as Celecoxib106. Moreover, Diacerein combined with Celecoxib demonstrates good safety and efficacy, with the ability to alleviate joint stiffness and improve body function at earlier stages of OA110. These findings suggest that combination therapy may have potential for early OA treatment. However, a recent multicenter, double-blind, placebo-controlled RCT confirmed that diacerein 50 mg twice daily for 24 weeks showed no significant improvement in pain in OA patients with MRI-confirmed effusion-synovitis, and the gastrointestinal adverse reaction rate was significantly higher than in the placebo group (41.7% vs 25.4%). Therefore, diacerein is only suitable for mild non-effusive early OA rather than inflammatory exudative OA109. Studies have also shown that OA patients experience pain relief after approximately 4 weeks of Diacerein treatment, with effects lasting for several months after discontinuation, indicating that the drug has a slower onset but a prolonged duration of action, suggesting a carry-over effect108,111,112. Additionally, compared to NSAIDs, Diacerein does not interfere with prostaglandin synthesis, exhibiting superior safety. Although Diacerein may cause mild to moderate adverse effects, its overall tolerability and safety are favorable108,112, making it a conditional alternative for mild non-inflammatory early OA patients.
IL-1 Ra
Significant progress has been made in the clinical development of IL-1 inhibitors. Orthokin, a product derived from incubating whole blood with CrSO₄-coated glass beads, enhances the synthesis of IL-1 receptor antagonist (IL-1Ra) and other anti-inflammatory cytokines. The administration method is intra-articular injection with a single injection volume of 2 mL, and twice weekly for three consecutive weeks113. In patients with knee OA, Orthokin treatment significantly improved symptoms and functional scores (Knee injury and Osteoarthritis Outcome Score, KOOS) compared to placebo, warranting further exploration as a potential cartilage-protective therapy113.
Autologous conditioned serum (ACS), which contains endogenous anti-inflammatory factors including IL-1Ra, has demonstrated efficacy in OA. Intra-articular ACS injection significantly alleviated symptoms and improved quality of life compared to hyaluronic acid or saline, with a safety profile comparable to saline114. Similarly, autologous IL-1Ra blood products (AILBPs) have been shown to be a safe and well-tolerated intra-articular treatment that effectively improves pain in mild-to-moderate OA115. Nevertheless, blood-derived products have inherent limitations, including heterogeneous patient populations, unstable product purity, and small sample sizes of clinical trials, which restrict their large-scale clinical promotion116,117.
However, not all IL-1-targeted therapies have translated positively from preclinical models. In a randomized controlled trial, the IL-1Ra Anakinra showed no statistically significant improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores over placebo, despite being well-tolerated118. Similarly, treatment with AMG 108, a monoclonal antibody targeting IL-1 receptor type I, led to a greater, though statistically nonsignificant, improvement in WOMAC pain scores compared with placebo. This may be attributed to the study's population having a low proportion of patients with high baseline pain. AMG 108 was well-tolerated and significantly reduced neutrophil counts, supporting its potential for further clinical investigation119.
IL-1 antibodies
Lutikizumab is a novel human bispecific variable domain immunoglobulin (DVD-Ig) that binds to and inhibits the activity of both IL-1α and IL-1β, aiming to alleviate OA pain and dysfunction. Previous studies have shown that after 16 weeks of treatment with 100 mg Lutikizumab, patients experienced significant improvements in WOMAC pain scores. However, in subsequent assessments, all groups showed a decrease in WOMAC scores, with no significant difference between the Lutikizumab and placebo groups. Additionally, when comparing the endpoint of synovitis and other symptoms between the Lutikizumab and placebo groups, no significant differences were found. Moreover, the incidence of adverse events (including injection site reactions, neutropenia, and drug discontinuation) in the Lutikizumab group was notably higher than that in the placebo group. These results suggest that while Lutikizumab may improve OA patients' pain symptoms to a limited extent, safety concerns remain120. Selective COX-2 inhibitors exhibit stable symptomatic relief effects in general OA populations, with definite gastrointestinal safety advantages over traditional NSAIDs121. Therefore, the application of Lutikizumab in OA treatment requires further research.
ABT-981 is a drug with a structure and mechanism of action very similar to Lutikizumab. Studies have shown that ABT-981 can reduce neutrophil counts, serum IL-1α/β levels, C-reactive protein, and MMP concentrations122. Compared to the placebo, the most common adverse reactions of ABT-981 were diarrhea, headache, and erythema at the injection site, with no severe events reported123. These results suggest that the drug has good safety and tolerability, making it a potentially better treatment option for patients with inflammation-driven OA.
In addition, patients treated with Canakinumab, a monoclonal antibody targeting IL-1, showed a significant reduction in the incidence of total knee or hip replacement surgery. Furthermore, patients who received Canakinumab treatment experienced a decrease in the incidence of cardiovascular events, with the most pronounced effects observed in those with the greatest reduction in high-sensitivity C-reactive protein (hs-CRP) and IL-6 levels124. This suggests that Canakinumab may be particularly suitable for patients who suffer from both OA and cardiovascular diseases.
Anti-IL-1 gene therapy
Gene therapy is an emerging advanced therapeutic modality for OA125. Genascence Company developed GNSC-001, an intra-articular sustained-release gene vector encoding IL-1Ra, which can continuously secrete anti-inflammatory factors in the joint cavity for more than 6 months. Pacira Biosciences designed lipid nanoparticle vectors to wrap IL-1Ra plasmids, improving chondrocyte transfection efficiency.
Biomarker-guided anti-IL-1 personalized therapy
Synovial fluid IL-1β, IL-1Ra, and MMP-3 are core inflammatory biomarkers for OA patient35,126. Patients with high synovial IL-1β concentration are defined as inflammatory OA phenotype, which is more sensitive to anti-IL-1 intervention124,127. Biomarker-guided patient screening can effectively improve clinical efficacy and reduce the risk of medication errors.
Combination therapy and anabolic synergistic strategy
Due to the complex cytokine network in OA, single IL-1 blockade cannot achieve ideal therapeutic effects128. The combination of anti-IL-1 drugs and anabolic factors (chondroitin sulfate) can simultaneously inhibit inflammation and promote cartilage matrix synthesis, significantly optimizing therapeutic outcomes. Novel structure-modifying molecules such as MIVD118 and SPR719 also show synergistic effects with anti-IL-1 therapy129.
Clinical translation barriers and future perspectives
Clinical translation challenges
Although anti-IL-1 drugs have excellent preclinical chondroprotective effects, clinical translation faces three core barriers: (1) OA disease heterogeneity, with obvious differences in inflammatory activity between early and late OA130 (2) short half-life of cytokine proteins and high therapeutic concentration, limiting drug enrichment131 (3) single-target therapy cannot break the inflammatory cytokine crosstalk loop132.
Biomaterial delivery prospect
To solve the short half-life defect of anti-IL-1 molecules, multiple biomaterial carriers have been developed, including hydrogel microspheres and lipid nanoparticles. These sustained-release biomaterials can prolong drug action time, reduce intra-articular injection frequency, and provide a new delivery strategy for anti-IL-1 therapy133,134.
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Inflammatory cytokines, particularly IL-1 and TNF, are established key drivers in OA pathogenesis, mediating degradation across cartilage, synovium, and bone. IL-1β, a principal mediator, activates NF-κB and MAPK pathways via IL-1RI, upregulating catabolic enzymes and pro-inflammatory factors that disrupt joint homeostasis and contribute to pain and structural decline. While anti-IL-1 therapies offer definite symptomatic relief and have lower gastrointestinal toxicity than traditional NSAIDs, they have unique adverse rea...
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The authors have no conflicts of interest to declare.
This study was supported by the Research Project of the Health Commission of Shanxi Province, China (2025YGYL015).
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