Enhancement of intervertebral disc cell senescence by WNT/β‐catenin signaling–induced matrix metalloproteinase expression
Open Access
- 8 June 2010
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatism
- Vol. 62 (10), 3036-3047
- https://doi.org/10.1002/art.27599
Abstract
Objective To determine whether intervertebral disc (IVD) cells express β-catenin and to assess the role of the WNT/β-catenin signaling pathway in cellular senescence and aggrecan synthesis. Methods The expression of β-catenin messenger RNA (mRNA) and protein in rat IVD cells was assessed by using several real-time reverse transcription–polymerase chain reaction, Western blot, immunohistochemical, and immunofluorescence analyses. The effect of WNT/β-catenin on nucleus pulposus (NP) cells was examined by transfection experiments, an MTT assay, senescence-associated β-galactosidase staining, a cell cycle analysis, and a transforming growth factor (TGFβ)/bone morphogenetic protein (BMP) pathway–focused microarray analysis. Results We found that β-catenin mRNA and protein were expressed in discs in vivo and that rat NP cells exhibited increased β-catenin mRNA and protein upon stimulation with lithium chloride, a known activator of WNT signaling. LiCl treatment inhibited the proliferation of NP cells in a time- and dose-dependent manner. In addition, there was an increased level of cellular senescence in LiCl-treated cells. Long-term treatment with LiCl induced cell cycle arrest and promoted subsequent apoptosis in NP cells. Activation of WNT/β-catenin signaling also regulated the expression of aggrecan. We also demonstrated that WNT/β-catenin signaling induced the expression of matrix metalloproteinases (MMPs) and TGFβ in NP cells. Conclusion The activation of WNT/β-catenin signaling promotes cellular senescence and may modulate MMP and TGFβ signaling in NP cells. We hypothesize that the activation of WNT/β-catenin signaling may lead to an increased breakdown of the matrix, thereby promoting IVD degeneration.Keywords
This publication has 45 references indexed in Scilit:
- Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitroJournal of Cell Science, 2006
- The Wnt-inducible Transcription Factor Twist1 Inhibits ChondrogenesisJournal of Biological Chemistry, 2006
- Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad NeighborsCell, 2005
- Growth Factors and Treatment of Intervertebral Disc DegenerationSpine, 2004
- The signals and pathways activating cellular senescenceThe International Journal of Biochemistry & Cell Biology, 2004
- Involvement of Wnt‐5a in chondrogenic pattern formation in the chick limb budDevelopment, Growth & Differentiation, 1999
- Notochordal Cells Interact with Nucleus Pulposus Cells: Regulation of Proteoglycan SynthesisExperimental Cell Research, 1999
- Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cellsCurrent Biology, 1996
- A molecular mechanism for the effect of lithium on development.Proceedings of the National Academy of Sciences, 1996
- The serial cultivation of human diploid cell strainsExperimental Cell Research, 1961