Galectin‐4: A Novel Mediator of Human Intervertebral Disc Degeneration

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ABSTRACT Background Intervertebral disc (IVD) degeneration is associated with severe clinical symptoms including chronic back pain. Galectins are a family of carbohydrate‐binding proteins, some of which can induce functional disease markers in IVD cells and other musculoskeletal tissues. Galectin‐4 and ‐8 were shown to trigger disease‐promoting activity in chondrocytes, but their effects on IVD cells have not been investigated yet. Methods IVD specimens from 36 patients with spondylosis, spondylolisthesis, and scoliosis were assessed immunohistochemically for the presence of galectin‐4 and ‐8. The degrees of radiological (Pfirrmann grade) and histopathological (Rutges score) degeneration of all specimens were correlated with histological galectin scores. To assess galectin functions, separate cell cultures of annulus fibrosus (AF) and nucleus pulposus (NP) ( n = 21) were established. Cell cultures were treated with recombinant galectin‐4, ‐8 (24 μg/mL), or Interleukin‐1β (IL‐1β) (10 ng/mL) and analyzed using RT‐qPCR and In‐Cell Western (ICW). Potential binding sites for galectins including sialylated N‐glycans and LacdiNAc structures were determined in AF and NP cells using liquid chromatography‐electrospray ionization‐tandem mass spectrometry (LC‐ESI‐MS/MS). Results The immunohistochemical presence of galectin‐4 in IVD specimens correlated with histopathological and clinical degeneration scores of patients, whereas galectin‐8 did not show significant correlations. Both galectins were detected across IVD compartments except for the endplate. In vitro, both galectins activated the nuclear factor‐kB pathway and induced functional disease markers (Interleukin‐8 (CXCL8) and matrix metalloproteinase‐3 (MMP3) mRNA). NP cells were more responsive to galectins and IL‐1β than AF cells, indicating region‐specific differences in galectin sensitivity. Conclusion This study identifies galectin‐4 as a novel molecular player in the pathogenesis of IVD degeneration.

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