GPNMB Suppresses Inflammation and Extracellular Matrix Degradation in Nucleus Pulposus Cells by Inhibiting Pro-Inflammatory Cytokine Production and Activation of the NF-κB Signaling Pathway.

Abstract

Lumbar disc herniation is primarily caused by intervertebral disc degeneration (IVDD). Nucleus pulposus (NP) cell dysfunction leads to pro-inflammatory cytokines secretion increase, causing extracellular matrix (ECM) degradation. ECM is essential for maintaining normal disc function. Glycoprotein (Transmembrane) Nmb (GPNMB) is strongly associated with inflammation, and its expression and effects in IVDD are unclear. We categorized 40 clinically collected IVDD samples using the magnetic resonance imaging (MRI)-based Pfirrmann grading system. GPNMB mRNA expression was notably suppressed in patients with severe IVDD compared with patients with mild IVDD. Increased GPNMB mRNA expression correlated with decreased Interleukin-6 (IL-6) expression and increased collagen type II (COL2A1) expression levels. We utilized lentivirus to overexpress GPNMB in IL-1β-induced NP cells to explore its function in IVDD. GPNMB overexpression inhibited pro-inflammatory cytokines Tumor necrosis factor-alpha and IL-6 secretion in IL-1β-induced NP cells, while anti-inflammatory cytokine IL-10 content was increased. In addition, GPNMB overexpression inhibited NP ECM degradation by decreasing ECM-degrading enzymes matrix metalloproteinases-3/13 and a disintegrin and metalloproteinase with thrombospondin motifs-4/5 in vitro. Mechanism studies revealed that GPNMB was bound to CD44, a receptor expressed on the NP cell surface. GPNMB overexpression inhibited nuclear factor-κB (NF-κB) p65 phosphorylation and nuclear translocation in vitro, possibly through CD44. In conclusion, GPNMB suppressed the expression of pro-inflammatory cytokines and ECM degradation in NP cells by inhibiting activation of NF-κB.