Spatiotemporal roles of IGFBP3 in intervertebral disc degeneration: from molecular mechanisms to potential therapeutic targets
Year: 2026
Type: article
Abstract: Intervertebral disc degeneration (IVDD) is a common pathological basis of chronic low back pain and remains a major challenge in spine care. Its biology involves extracellular matrix (ECM) metabolic dysregulation, chronic inflammatory remodeling of the disc microenvironment, oxidative stress, and cellular senescence. Within this complex milieu, insulin-like growth factor-binding protein 3 (IGFBP3) appears to exert context-dependent effects, which have been described as a “paradoxical” or “dual” role. This review aims to synthesize the available evidence regarding IGFBP3 in IVDD and related models, with particular attention to evidence hierarchy, biological context, and the limitations of cross-model extrapolation. Rather than defining a fixed chronological switch from “protective” to “deleterious,” we discuss a context-dependent framework in which IGFBP3-related effects may vary according to disc cell phenotype, inflammatory burden, oxidative stress, senescence status, and duration of exposure. Current evidence suggests that IGFBP3 may be involved in several processes relevant to disc homeostasis, but the strength of evidence differs substantially across pathways. IVDD-specific evidence is strongest for the association of IGFBP3 with inflammatory and senescence-related disc phenotypes, particularly interferon/JAK-STAT-related remodeling and SASP-associated degeneration. NF-κB-related inflammation represents an important downstream inflammatory axis in IVDD, whereas TGF-β/Smad-related ECM anabolism, MMP/TIMP modulation, mitochondrial quality control, ROS regulation, macrophage polarization, and MSC homing are best interpreted as secondary, context-dependent, or hypothesis-generating mechanisms when supported mainly by non-IVDD models. Thus, IGFBP3 is discussed not as a pan-regulatory factor but as a context-sensitive node whose relevance depends on pathway hierarchy and disc microenvironmental state. The function of IGFBP3 appears to be highly context-dependent. Available evidence suggests that IGFBP3 may participate in reparative programs under certain transient or moderate stress conditions, whereas sustained upregulation in chronically inflamed or senescence-associated microenvironments may be linked to SASP amplification and degeneration-related remodeling. Consequently, future therapeutic strategies should not rely on simple factor supplementation or blockade. Instead, emphasis should be placed on stage-stratified validation and smart responsive materials that can fine-tune IGFBP3-related pathways within an appropriate therapeutic window while minimizing the risk of accelerating senescence-associated inflammation.
Institutions: Wuhan Sports University, Wuhan University, Wuhan Third Hospital
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,090
OpenAlex ID: W7203917352
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