The underlying mechanisms that stimulate the alteration of chondrocytes and subsequent cartilage breakdown in osteoarthritis (OA) remain fully elucidated; however, these cellular alterations are heavily supposed to contribute to the progressive destruction of joint tissue in OA [29]. The extracellular regulated kinase (ERK) cascade represents one of the most complex signaling axes within the joint microenvironment, and accumulated evidence has shown that the pathological activation of this pathway directly relates to the pathogenesis and progression of OA. According to previous studies, a much higher phosphorylation (activation) level of ERK is consistently captured in tissue exhibiting a greater degree of OA compared with normal tissue, thereby indicating that it plays an important role in the destruction of articular cartilage [30].

Mechanistically, the abnormal phosphorylation of ERK stimulates activator protein 1 (AP-1) activation. This downstream nuclear event results in reduced chondrocyte proliferation, diminished type II collagen synthesis, and suppressed proteoglycan production, while simultaneously driving the increased expression of cartilage-degrading enzymes, most notably matrix metalloproteinase (MMP)-13. A growing body of reports has indicated that such MMP-13 overproduction by chondrocytes holds a central and indispensable role in the degeneration of cartilage matrix [29]. Characterizing the intermediates of this cascade, Otero et al. [30] speculated that E74-like factor 3 (ELF3) acts as a critical MEK/ERK downstream effector, which stimulates abnormal MMP13 expression and activity in chondrocytes and other joint cell types when they respond to environmental stress and inflammatory stimuli. Therefore, the precise regulation of the MEK/ERK/ELF3 signaling pathway may be one of the key contributing factors governing the development and phenotypic progression of human OA.

While cartilage erosion is the hallmark of OA, the joint functions as an integrated organ; consequently, the hyperactivation of ERK signaling exerts distinct, cell-type-specific effects across different cellular compartments within the joint microenvironment, shifting the entire joint toward a catabolic state.

Articular Chondrocytes: Within the cartilage layer, altered ERK activity disrupts homeostatic maintenance. Takagi et al. reported that the upregulated activation of ERK, p38, and STAT3 cascades can induce IL-6 and RANKL expressions, which are directly related to cartilage destruction-related processes, including phenotypic dedifferentiation and chronic inflammatory responses in OA chondrocytes [31]. This sustained ERK activation shifts chondrocytes from an anabolic phenotype to a hypertrophic and senescent state, accelerating cartilage matrix collapse.

Synovial Fibroblasts: In fibroblast-like synoviocytes (FLSs), abnormal ERK activation serves as a major driver of synovitis. Responding to mechanical overload and alarmins, hyperphosphorylated ERK in FLSs accelerates the transcription of pro-inflammatory cytokines and chemokines, establishing a deleterious feed-forward inflammatory loop that aggravates joint pain and swelling.

Subchondral Bone Cells: Beneath the tidemark, ERK signaling in subchondral osteoblasts and osteoclasts modulates aberrant bone remodeling. Pathological ERK activation in osteoblasts enhances abnormal osteogenesis, contributing to the subchondral bone sclerosis and marginal osteophyte formation that characterize advanced OA stages.

The intracellular ERK cascade does not operate in isolation; rather, it is embedded in a complex crosstalk network involving various inflammatory cytokines, adipokines, and stress-induced kinases that synergistically accelerate cartilage breakdown.

Prostaglandin E2 (PGE2) represents a primary inflammatory mediator downstream of this network. Masuko-Hongo et al. [32] reported that activating ERK and p38 signaling cascades significantly promotes the formation of PGE2, which possesses several functions involved in cartilage breakdown in OA patients, including the modulation of proteoglycan and collagen synthesis and the stimulation of chondrocyte apoptosis. Furthermore, metabolic factors heavily intersect with this pathway; Hui et al. [33] reported that the adipokine leptin plays a critical role in the inflammatory and degenerative processes in cartilage degradation via the upregulation of proteolytic enzymes with a concomitant activation of STAT1, STAT3, STAT5, MAPK (JNK, ERK, p38), AKT, and NF-κB signaling pathways.

This catabolic cascade is prominently fueled by upstream alarming cytokines. Dai et al. reported that IL-1β and TNF-α induce the levels of MMP1, MMP3, MMP13, ADAMTS4, and ADAMTS5 transcription, playing important roles in cartilage degradation in OA [34]. Intriguingly, these destructive effects are inhibited by the depletion of Brd4 and Brd3 through suppressing the downstream NF-κB, JNK, and ERK signaling pathways [34]. Furthermore, cellular stress kinases directly feed into this axis; Ma et al. [35] reported that the double-stranded (ds) RNA-dependent protein kinase (PKR) leads to OA pathogenesis by regulating critical molecular events, including oxidative stress (characterized by elevated NOX expression and ROS formation), inflammatory responses, and matrix degradation, through inducing the ERK/NF-κB signaling axis. Additionally, epigenetic modulators tightly control this cascade. Wang et al. suggested that histone deacetylase (HDAC) 4 and HDAC 8 may serve as key upstream mediators of JNK and ERK in regulating the IL-1β-induced cartilage catabolic changes and degradation [9].

Due to their prominent ERK-targeting efficacy, potent anti-inflammatory potential, and low adverse reaction profiles, natural plant extracts and phytochemicals have been widely explored as candidate therapeutic agents in OA management.

Ma et al. [36] reported that isorhapontigenin (ISO), a natural stilbene derivative, suppresses interleukin-1β (IL-1β)-induced elevation of nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX2), matrix metalloproteinases (MMPs), and ADAMTS5 in rat chondrocytes. Crucially, ISO mitigates IL-1β-induced inflammation and cartilage matrix damage by suppressing the activation of ERK and p38 signaling pathways. Similarly, Zhou et al. [37] investigated the chondroprotective effects of kinsenoside (Kin) to attenuate OA progression, demonstrating that Kin inhibits the core MAPK signaling molecules p-JNK, p-ERK, and p-P38, thereby alleviating IL-1β-induced chondrocyte damage. Wongwichai et al. [38] showed that anthocyanins and their metabolites extracted from purple rice can inhibit IL-1β-induced MMP expression by significantly blocking IκBα degradation, NF-κB/p65 phosphorylation, and ERK signaling axis activation. Emodin, an anthraquinone isolated from Radix et Rhizoma Rhei, has long been used in traditional medicine; Liu et al. [39] evaluated its effects on inflammatory mediators in rat chondrocytes, revealing that emodin stimulates chondrocyte proliferation by suppressing the concurrent activation of ERK and Wnt/β-catenin signaling while downregulating downstream inflammatory targets. Furthermore, Huang et al. [40] revealed that Kaempferol significantly dampens the IL-1β-induced expression of inflammatory mediators (such as COX2) and common matrix-degrading enzymes (MMP-1, MMP-3, and MMP-13) via the pharmacological inhibition of mitogen-activated protein kinase-associated ERK and P38 pathways, suggesting its utility as a novel therapeutic agent. Investigating Schisandra chinensis, Ran et al. [41] demonstrated that its primary active component, Schisandrin B, decreases the IL-1β-induced upregulation of MMP-3, MMP-13, IL-6, and iNOS, while simultaneously rescuing the expression of Collagen II and Aggrecan. These protective effects were mediated by a significant decrease in the phosphorylation levels of p38, ERK, JNK, and NF-κB/p65, along with the suppression of NF-κB/p65 nuclear translocation.

Beyond these compounds, echinocystic acid (EA), a pentacyclic triterpene extracted from the fruits of Gleditsia sinensis Lam, exerts versatile anti-inflammatory and antioxidant actions. Ma et al. [42] demonstrated that EA successfully inhibits the IL-1β-stimulated production of MMP-13, NO, and PGE2, as well as the protein expression of iNOS and COX-2 in chondrocytes, via the dual inactivation of NF-κB and MAPK (JNK, p38, and ERK) cascades. Additionally, Zhao et al. [43] demonstrated that gentiopicroside exhibits a potent protective effect against IL-1β-induced inflammatory responses and enhances Type II Collagen expression by inhibiting the p38, ERK, and JNK branches of IL-1β transduction in rat chondrocytes.

Modulating ERK signaling via endogenous gaseous transmitters or specific neuro-immunological receptor pathways represents another innovative pharmacological frontier in OA therapy.

Gasotransmitters have garnered attention for their homeostatic roles; Ha et al. [44] investigated the therapeutic efficacy of hydrogen sulfide (H2S) in OA, revealing that H2S markedly reverses the detrimental effects of IL-1β on MMP-13, PGE2, and NO production, alongside suppressing the gene transcription of COX-2, MMP-13, and iNOS. Mechanistically, H2S achieved these effects by directly inhibiting the IL-1β-induced activation of the ERK/IκBα/NF-κB pathway. Concurrently, targeting cholinergic anti-inflammatory pathways has yielded promising results. Liu et al. [45] demonstrated that the inhibition of chondrocyte activation can be achieved via the stimulation of alpha-7 nicotinic acetylcholine receptors (α7-nAChRs). Their data indicated that nicotine administration suppresses monoiodoacetate (MIA)- or IL-1β-induced chondrocyte hyperactivation via the α7-nAChR, coupled with a distinct decrease in the resulting phosphorylation of p38, ERK, JNK, and NF-κB p65.

The therapeutic modulation of the ERK axis can also be orchestrated using endogenous biological proteins, circadian hormones, and epigenetic or enzymatic modulators that dictate joint homeostasis.

Lactoferrin (LF) serves as a prominent marker of neutrophil granulocyte activation, maintaining high concentrations in the synovial fluid of arthritic joints. Zhang et al. [46] provided the first evidence demonstrating that LF activates bone morphogenetic protein 7 (BMP7) expression specifically through the ERK pathway, wherein the classical ERK inhibitor U0126 completely abrogates LF-mediated activation of the BMP7 gene in primary articular chondrocytes. Examining circadian hormones, Lim et al. [47] analyzed the impact of melatonin in hydrogen peroxide (H₂O₂)-challenged human chondrocytes and rabbit OA models, establishing that melatonin induces cytoprotection and exerts anti-inflammatory effects against H₂O₂-stimulated cytotoxicity, iNOS, and COX-2 via the extensive downregulation of PI3K/AKT, p38, ERK, JNK, and NF-κB signaling.

Conversely, epigenetic and enzymatic targets are critical regulators of this axis. SIRT2, a cytoplasm-localized mammalian sirtuin family member, plays an intriguing role; Eo et al. [48] indicated that SIRT2 induction provokes a loss of Type II Collagen, decreases sulfated proteoglycan levels, and incites inflammatory responses by inducing COX-2 and PGE2 expression. Strikingly, the direct inhibition of ERK using PD98059 suppressed SIRT2-mediated dedifferentiation and COX-2 expression in articular chondrocytes. In contrast, viral transduction of lysyl oxidase-like 2 (LOXL2) in OA chondrocytes by Alshenibr et al. [49] inhibited chondrocyte apoptosis and upregulated the mRNA levels of chondroitin sulfate proteoglycan (CSPG4), aggrecan (ACAN), SOX9, and COL2A1, while reducing MMP-1, MMP-3, and MMP-13 levels by blunting TGF-β1-induced ERK phosphorylation and IL-1β-induced phospho-NF-κB/p65.

Furthermore, metabolic components and cytokines profoundly interact with this signaling network. Lai et al. [50] demonstrated that physiological concentrations of soluble uric acid (sUA) render anti-inflammatory and chondroprotective actions via the inhibition of the ERK/AP-1 signaling axis. Focusing on structural tissues, Xiong et al. [51] showed that ERK inhibition exerts therapeutic efficacy against the deleterious degradative effects of the macrophage migration inhibitory factor (MIF)-CD74 signal in human degenerated cartilage endplate (CEP) tissues. Shkhyan et al. [52] showed that the drug-induced modulation of glycoprotein 130 (gp130) signaling diminishes apoptosis, hypertrophic differentiation, and cartilage matrix breakdown by suppressing IL-6-mediated activation of ERK and NF-κB cascades. Finally, inhibiting angiopoietin-like protein 2 (aNgPtl2) using specific inhibitors dramatically downregulates inflammation-related gene expressions by halting the phosphorylation of ERK, JNK, p38, AKT, and NF-κB [53], while the novel cytokine IL-37 suppresses pro-inflammatory factor expression via the IL-1R8 receptor by inactivating p38, ERK, JNK, and NF-κB pathways [54].

Because excessive mechanical loading is a primary physical driver of OA pathogenesis, intervening in mechanotransduction cascades linked to ERK represents a highly physiologically relevant strategy.

Hirose et al. [55] reported that excessive mechanical stimulation activates cell-surface integrins (αVβ3 and αVβ5) on chondrocytes, thereby triggering a severe inflammatory cascade that upregulates IL-1β, TNF-α, MMP-3, and MMP-13. Crucially, this mechanical stress-induced acceleration was significantly suppressed by treatment with cilengitide, which acts by blocking the phosphorylation of focal adhesion kinase (FAK) and downstream MAPKs (ERK, JNK, and p38). In the context of high-magnitude cyclic tensile strain (CTS), Sumi et al. [56] examined the role of semaphorin 3A (Sema3A), discovering that exogenous Sema3A administration effectively inhibits CTS-upregulated inflammatory cytokine transcription and downregulates the mechanical activation of AKT, ERK, and NF-κB in a dose-dependent manner. Complementing this, Yanoshita et al. [57] suggested that FAK directly regulates inflammatory factors such as COX-2, IL-1β, and TNF-α in chondrocytes subjected to CTS by dynamically modulating the phosphorylation of FAK, p38, ERK, and JNK.

Modern biomedical strategies utilizing non-coding RNAs or stem cell-derived nanovesicles have expanded the therapeutic toolset for precision targeting of the ERK axis in OA.

MicroRNAs serve as critical post-transcriptional regulators of joint cartilage homeostasis. Rasheed et al. [58] demonstrated that transfecting chondrocytes with a miR-125b mimic in the presence of IL-1β significantly dampens the secretion of multiple pro-inflammatory cytokines, chemokines, and growth factors―including IL-6, IL-8, INF-γ, IGFBP-1, and PDGF-BB. This broad anti-inflammatory effect was mediated through the inhibition of p38, JNK, and ERK phosphorylation, along with the reduction of nuclear levels of NF-κBp50 and NF-κBp65. Additionally, the therapeutic deployment of cell-free biologicals has emerged as a frontline option; Qi et al. [59] analyzed the utility of bone mesenchymal stem cell-derived exosomes (BMSC-Exos) on chondrocyte viability under both physiological and inflammatory settings. Their study demonstrated that BMSC-Exos treatment significantly protects chondrocytes by inhibiting the pathological phosphorylation of p38 and ERK, while concurrently promoting the prosurvival phosphorylation of AKT.