ZIP8 mediates the extracellular matrix degradation of nucleus pulposus cells via NF-κB signaling pathway

Abstract

The extracellular matrix (ECM) degradation of nucleus pulposus cells (NPCs) is mainly induced by metalloproteinases (MMPs). Zn²⁺ is an essential component of MMPs, but the effect of Zn²⁺ importers in controlling ECM metabolism remains unclear. The purpose of this research was to identify the involvement of Zn²⁺ importers in ECM degradation induced by inflammatory stimuli and excessive mechanical stressing. In this study, NPCs from Sprague-Dawley (SD) rats were separated and cultured. FluoZin-3 AM staining was applied to detect [Zn²⁺]i in NPCs treated with Interleukin-1β (IL-1β) or cyclic tensile strain (CTS) with a Flexcell Strain Unit. We found that intracellular Zn²⁺ concentration ([Zn²⁺]i) elevated dramatically, and ZIP8 is the predominant Zn²⁺ importer among all importers in senescent NPCs. The [Zn²⁺]i and MMP expression level both increased in IL-1β and CTS treated NPCs. Furthermore, the expression of ZIP8 was also markedly increased. However, knockdown of ZIP8 with siRNA alleviated ECM degradation induced by inflammatory stimuli and CTS. Both stimuli activated NF-κB signaling pathway, and knockdown of ZIP8 effectively inhibited NF-κB signaling pathway activation. In conclusion, knockdown of ZIP8 can alleviate NPCs' ECM degradation caused by inflammatory stimuli and excessive mechanical stressing.

Keywords: Extracellular matrix; Metalloproteinase; Nucleus pulposus cell; ZIP8; Zinc.