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.