Inhibition of Rac1 activity by NSC23766 prevents cartilage endplate degeneration via Wnt/β-catenin pathway

J Cell Mol Med. 2020 Mar;24(6):3582-3592. doi: 10.1111/jcmm.15049. Epub 2020 Feb 10.

Abstract

Cartilage endplate (CEP) degeneration has been considered as one of important factors related to intervertebral disc degeneration (IVDD). Previous researches have showed that Rac1 played a pivotal role in chondrocyte differentiation. However, the effect of Rac1 during the process of CEP degeneration remains unclear. Herein, we explored the effect of Rac1 on CEP degeneration and elucidated the underlying molecular mechanism. We found expression of Rac1-GTP increased in human-degenerated CEP tissue and IL-1β-stimulated rat endplate chondrocytes (EPCs). Our study revealed that Rac1 inhibitor NSC23766 treatment promoted the expression of collagen II, aggrecan and Sox-9, and decreased the expression of ADTAMTS5 and MMP13 in IL-1β-stimulated rat EPCs. Moreover, we also found that NSC23766 could suppress the activation of Wnt/β-catenin pathway, suggesting that the beneficial effects of Rac1 inhibition in EPCs are mediated through the Wnt/β-catenin signalling. Besides, puncture-induced rats models showed that NSC23766 played a protective role on CEP and disc degeneration. Collectively, these findings demonstrated that Rac1 inhibition delayed the EPCs degeneration and its potential mechanism may be associated with Wnt/β-catenin pathway regulation, which may help us better understand the association between Rac1 and CEP degeneration and provide a promising strategy for delaying the progression of IVDD.

Keywords: NSC23766; Rac1; Wnt/β-catenin; cartilage endplate; intervertebral disc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / pharmacology*
  • Animals
  • Cartilage / drug effects
  • Cartilage / pathology*
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Disease Models, Animal
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Humans
  • Interleukin-1beta / pharmacology
  • Intervertebral Disc Degeneration / metabolism*
  • Intervertebral Disc Degeneration / pathology
  • Intervertebral Disc Degeneration / prevention & control*
  • Pyrimidines / pharmacology*
  • Rats, Sprague-Dawley
  • SOX9 Transcription Factor / metabolism
  • Wnt Signaling Pathway* / drug effects
  • beta Catenin / metabolism
  • rac1 GTP-Binding Protein / antagonists & inhibitors*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Aminoquinolines
  • Interleukin-1beta
  • NSC 23766
  • Pyrimidines
  • SOX9 Transcription Factor
  • beta Catenin
  • rac1 GTP-Binding Protein