Chondrocyte and Disc Biology
Conditional activation of β-catenin signaling in mice leads to severe defects in intervertebral disc tissue
Version of Record online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2611–2623, August 2012
How to Cite
Wang, M., Tang, D., Shu, B., Wang, B., Jin, H., Hao, S., Dresser, K. A., Shen, J., Im, H.-J., Sampson, E. R., Rubery, P. T., Zuscik, M. J., Schwarz, E. M., O'Keefe, R. J., Wang, Y. and Chen, D. (2012), Conditional activation of β-catenin signaling in mice leads to severe defects in intervertebral disc tissue. Arthritis & Rheumatism, 64: 2611–2623. doi: 10.1002/art.34469
- Issue online: 27 JUL 2012
- Version of Record online: 27 JUL 2012
- Accepted manuscript online: 15 MAR 2012 11:01AM EST
- Manuscript Accepted: 6 MAR 2012
- Manuscript Received: 11 OCT 2010
- National Basic Research Program of China. Grant Number: 973 Program grant 2010cb530400
- NIH. Grant Numbers: R01-AR-055915, R01-AR-054465, R01-AR051189
- New York State Department of Health and the Empire State Stem Cell Board. Grant Number: C024320
The incidence of low back pain is extremely high and is often linked to intervertebral disc (IVD) degeneration. The mechanism of this disease is currently unknown. This study was undertaken to investigate the role of β-catenin signaling in IVD tissue function.
β-catenin protein levels were measured by immunohistochemical analysis of disc samples obtained from patients with disc degeneration and from normal subjects. To generate β-catenin conditional activation (cAct) mice, Col2a1-CreERT2–transgenic mice were bred with β-cateninfx(Ex3)/fx(Ex3) mice. Changes in disc tissue morphology and function were examined by micro–computed tomography, histologic analysis, and real-time polymerase chain reaction assays.
β-catenin protein was up-regulated in disc tissue samples from patients with disc degeneration. To assess the effects of increased β-catenin levels on disc tissue, we generated β-catenin cAct mice. Overexpression of β-catenin in disc cells led to extensive osteophyte formation in 3- and 6-month-old β-catenin cAct mice, which were associated with significant changes in the cells and extracellular matrix of disc tissue and growth plate. Gene expression analysis demonstrated that activation of β-catenin enhanced runt-related transcription factor 2–dependent Mmp13 and Adamts5 expression. Moreover, genetic ablation of Mmp13 or Adamts5 on the β-catenin cAct background, or treatment of β-catenin cAct mice with a specific matrix metalloproteinase 13 inhibitor, ameliorated the mutant phenotype.
Our findings indicate that the β-catenin signaling pathway plays a critical role in disc tissue function.