Unraveling the mechanisms of intervertebral disc degeneration: an exploration of the p38 MAPK signaling pathway

The paper addresses the pervasive burden of intervertebral disc degeneration (IDD), the principal cause of chronic low back pain worldwide. It outlines multifactorial risk factors—including heredity, infection, sex, obesity, smoking, aging, and aberrant mechanical load—and emphasizes microenvironmental changes in IVD (cellular and biochemical) that precipitate ECM breakdown, cellular apoptosis/senescence, and structural damage. The anatomical context of IVD (nucleus pulposus, annulus fibrosus, cartilaginous endplate) and the characteristic degenerative cascade (proteoglycan loss, collagen II-to-I shift, dehydration, annular fissures, endplate ossification, impaired nutrient exchange) are reviewed. Conventional treatments focus on symptom relief rather than modifying disease mechanisms. The review’s purpose is to elucidate the role of the p38 MAPK pathway—one branch of MAPK signaling—across major IDD processes (inflammation, ECM metabolism, apoptosis, senescence, oxidative stress, autophagy, proliferation, migration/differentiation) to identify therapeutic targets that may modify disease progression.

As a narrative review, the article synthesizes extensive prior research implicating p38 MAPK signaling in IDD pathophysiology. It details how inflammatory mediators (e.g., IL-1β, TNF-α, IL-6), mechanical and osmotic stresses, hyperglycemia, and oxidative stress activate p38 MAPK in IVD cells, driving catabolic enzyme expression (MMPs, ADAMTS), ECM loss, and pain mediators (PGE2). Studies using p38 inhibitors (e.g., SB203580, SB202190) demonstrate reductions in inflammatory cytokines, PGE2, and matrix catabolism. Isoform-specific roles (p38α/β vs. δ) in catabolic responses are discussed. Literature on cellular senescence shows p38 activation correlates with increased p16INK4a, p53, and SA-β-Gal and is induced by acidic pH and high-magnitude compression. Oxidative stress studies link ROS accumulation to p38-mediated KMT2D phosphorylation, increasing MMPs and ECM degradation; antioxidants (NAC) counteract these effects. Additional literature shows p38 involvement in apoptosis (including inflammatory and mechanical triggers), autophagy crosstalk, cell proliferation inhibition, macrophage chemokine regulation (CCL3/CCL4), and macrophage polarization. The review compiles evidence for various modulators (e.g., OP-1, IL-10, RhTSG-6, hyperbaric oxygen, allicin, quercetin, MSC-conditioned medium, MGF peptide) that act via p38 to mitigate degeneration.

- p38 MAPK activation is elevated in degenerated IVD tissue and is triggered by IDD-relevant stimuli (inflammatory cytokines, mechanical stress, hypertonic and acidic conditions, high glucose, oxidative stress). - Inflammation: p38 mediates cytokine-induced responses in NPCs/AF cells; inhibitors (SB203580/SB202190) reduce IL-6, PGE2, and MMPs and blunt IL-1β/TNF-α catabolic effects. p38 activates downstream NF-κB/AP-1 to increase IL-1β, IL-6, TNF-α; IL-10 suppresses p38 activation and delays IDD. - ECM metabolism: p38 drives expression of catabolic enzymes (ADAMTS-4/-5; MMP1/3/13) and decreases anabolic matrix components (collagen II, proteoglycans). Isoforms p38α/β promote catabolic gene expression; p38δ may oppose. p38 or ERK inhibition prevents cytokine-induced ECM breakdown. - Senescence: p38 activation correlates with senescence markers (p16, p53, SA-β-Gal). Acidic pH (pH 6.2) and high compression activate p38, reduce proliferation/telomerase, and increase senescence; SB203580 reverses these effects. - Oxidative stress: ROS promotes p38-mediated phosphorylation of KMT2D, enhancing MMP3/9/13 and ECM degradation; antioxidants reverse catabolic effects. Allicin protects NP cells from AOPP-mediated oxidative injury via p38 inhibition. - Proliferation: p38 activation (e.g., by H2O2 or hypertonicity) induces cell cycle arrest (G1/G2), decreases telomerase activity, and inhibits proliferation; p38 inhibition partially restores proliferation under high compression. - Apoptosis: p38 signaling contributes to apoptosis of NP/AF/CEP cells under inflammatory, high glucose, or mechanical stresses. Modulators such as RhTSG-6, miR-15a, quercetin (via p38–autophagy), DHJSD, and MGF peptide reduce apoptosis by inhibiting p38. - Autophagy: p38 interacts with autophagy pathways; quercetin induces protective autophagy and reduces apoptosis/ECM loss through partial p38 inhibition. - Migration/differentiation: p38 regulates chemokines (CCL3/CCL4) driving macrophage infiltration and influences macrophage polarization (M1) via p38α/β. p38/ERK alterations affect AF cell differentiation; leptin promotes AF terminal differentiation via p38/ERK. - Therapeutic modulators acting via p38 include OP-1 (reduces apoptosis, enhances matrix synthesis), IL-10, RhTSG-6, hyperbaric oxygen (reduces MMPs and NO), allicin, baicalein, quercetin, MSC-conditioned medium, and MGF peptide, suggesting p38 as a viable target for disease-modifying therapies.

The review integrates mechanistic evidence that p38 MAPK is a central hub linking inflammatory signaling, ECM catabolism, cellular senescence/apoptosis, oxidative stress, autophagy, and cell proliferation/migration in IVD degeneration. By demonstrating that p38 activation both initiates and sustains degenerative cascades (e.g., cytokine feedback, MMP/ADAMTS upregulation, ROS amplification), the findings support targeting p38 to interrupt vicious cycles driving IDD progression. Preclinical data show that p38 inhibition or modulation attenuates inflammatory mediators, preserves ECM, reduces apoptosis and senescence, and can restore anabolic balance. Isoform specificity (p38α/β vs δ) offers opportunities for more precise interventions. Overall, the evidence positions p38 MAPK as a promising therapeutic axis to modify disease rather than merely alleviate symptoms.

The review concludes that p38 MAPK is actively involved across key pathogenic processes of IDD—promoting inflammation, ECM degradation, oxidative stress responses, programmed cell death, and cellular senescence—and that its modulation can ameliorate these processes. Numerous agents and conditions that inhibit or modulate p38 demonstrate protective effects on IVD cells and matrix, underscoring the pathway’s potential as a therapeutic target. Future work should define precise molecular targets within the p38 axis (including isoform-specific roles), clarify upstream and downstream effectors (including cytokines and non-coding RNAs), and develop strategies to achieve selective modulation that preserves normal cell physiology while mitigating degenerative signaling. Deeper mechanistic studies are needed to translate pathway insights into safe, effective, targeted therapies for IDD.

- The review highlights that specific regulatory targets and mechanisms within the p38 MAPK pathway remain incompletely defined (e.g., how particular drugs exert effects through p38 in detail). - p38 MAPK participates in multiple parallel processes (inflammation, apoptosis, autophagy, proliferation), posing challenges for selective therapeutic targeting without disrupting normal physiology. - Isoform-specific functions and context-dependent effects (cell type, stimulus intensity/duration) complicate generalization and clinical translation. - Lack of standardized methodologies or comprehensive clinical data limits direct extrapolation from in vitro/in vivo models to patients; more precise mechanistic and translational studies are required.