The relationship between the Wnt/β-catenin and TGF-β/BMP signals in the intervertebral disc cell.

Abstract

Degeneration of the lumbar intervertebral disc (IVD) is a cause of low back pain. In osteoarthritis patients, an increase in β-catenin accumulation has been reported. However, the molecular mechanisms involved in IVD remain unclear. In the present study, we examined the relationship of Wnt/β-catenin and transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signals in the IVDs. We found that treatment of nucleus pulposus (NP) cells with the Wnt/β-catenin activator lithium chloride (LiCl) results in the increased expression of β-catenin mRNA and protein, and cell proliferation is decreased due to the activation of the Wnt/β-catenin signals through the suppression of c-myc and cyclin-D1. In addition, T-cell-specific transcription factor (TCF) promoter activity was found to increase the following stimulation with LiCl alone, and was further increased when BMP2 was added, in comparison to the control group. We further observed the effects of treatment with PD98059, a specific inhibitor of the mitogen-activated protein kinase pathway, on TCF promoter activity in NP cells. These effects were largely attenuated by PD98059. Moreover, when transfected IVDs were co-transfected with R-Smad expression plasmids, there was a significant decrease in TCF reporter activity. We thereafter evaluated the effects of increased Wnt/β-catenin activity on the transcriptional activity of the Smad binding element (SBE). As a result, LiCl suppressed the activity of SBE reporter activity. The present study demonstrates for the first time that there are opposing effects between the Wnt/β-catenin and TGF-β/BMP signals in IVDs, which is consistent with the Wnt/β-catenin signals contributing to the pathogenesis of IVD degeneration.

• Authors: Akihiko Hiyama, Daisuke Sakai, Masahiro Tanaka, Fumiyuki Arai, Daisuke Nakajima, Koichiro Abe, Joji Mochida
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 226 Issue 5 Pg. 1139-48 (May 2011) ISSN: 1097-4652 [Electronic] United States
• PMID: 20945354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

• Bone Morphogenetic Protein 2
• Ccnd1 protein, rat
• Ctnnb1 protein, rat
• Flavonoids
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• RNA, Messenger
• Smad Proteins, Receptor-Regulated
• TCF Transcription Factors
• Transforming Growth Factor beta
• Wnt Proteins
• Wnt3 Protein
• beta Catenin
• Cyclin D1
• Extracellular Signal-Regulated MAP Kinases
• Lithium Chloride
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Bone Morphogenetic Protein 2 (metabolism)
• Cell Line
• Cell Proliferation
• Cyclin D1 (metabolism)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Female
• Flavonoids (pharmacology)
• Intervertebral Disc (drug effects, metabolism)
• Intervertebral Disc Degeneration (metabolism)
• Lithium Chloride (pharmacology)
• Mice
• Promoter Regions, Genetic
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-myc (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Smad Proteins, Receptor-Regulated (genetics, metabolism)
• TCF Transcription Factors (genetics, metabolism)
• Time Factors
• Transcriptional Activation
• Transfection
• Transforming Growth Factor beta (metabolism)
• Wnt Proteins (genetics, metabolism)
• Wnt3 Protein
• beta Catenin (genetics, metabolism)