Aggrecan remodeling in degenerate discs: Patterns, determinants, measurement, and emerging therapies

Aggrecan is the principal determinant of water retention in the nucleus pulposus and a core regulator of intervertebral disc mechanics. This review synthesizes evidence on aggrecan alterations during intervertebral disc degeneration (IVDD), associated upstream drivers, and current approaches for assessment and therapy. Based on published literature, we present the first comprehensive, 4-part classification of aggrecan modifications observed across degeneration: (1) a reduced chondroitin sulfate–to–keratan sulfate ratio; (2) increased enzymatic cleavage of the core protein; (3) decreased core protein expression; and (4) exacerbated hyaluronic acid degradation. These shifts converge on loss of fixed charge density and osmotic pressure, reduced water content, and altered tissue mechanics in the degenerating disc. We further provide the first integrative synthesis of upstream drivers linked to these aggrecan alterations, systematizing them into a convergent set that includes hypoxia, metabolic dysregulation with lactate accumulation and acidosis, inflammatory cytokine signaling, and osmotic imbalance. For assessment, we outline conventional biochemical/chemical assays for proteoglycans and glycosaminoglycans and summarize emerging readouts that infer aggrecan or glycosaminoglycan content and may aid early evaluation. From a therapeutic standpoint, current strategies fall into 2 broad categories. Restorative approaches attempt to mitigate 1 or more modification domains—most commonly via anti-inflammatory signaling control or modulation of matrix-degrading enzymes—but typically focus on single targets and may not address the multifactorial nature of degeneration. Substitution approaches seek to supplement water-retaining function with aggrecan-mimicking materials; although several candidates reproduce key biophysical features in vitro, in vivo validation in disc models remains limited. Collectively, these findings position aggrecan as a molecular and biophysical anchor for understanding IVDD and designing interventions. Future work should prioritize multitarget repair strategies that address the convergent drivers identified here and support in vivo evaluation of aggrecan substitutes to restore osmotic function and matrix homeostasis in nucleus pulposus (NP).