Open AccessConditional activation of β‐catenin signaling in mice leads to severe defects in intervertebral disc tissue
Author(s) -
Wang Meina,
Tang Dezhi,
Shu Bing,
Wang Baoli,
Jin Hongting,
Hao Suyang,
Dresser Karen A.,
Shen Jie,
Im HeeJeong,
Sampson Erik R.,
Rubery Paul T.,
Zuscik Michael J.,
Schwarz Edward M.,
O'Keefe Regis J.,
Wang Yongjun,
Chen Di
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34469
Subject(s) - intervertebral disc , catenin , extracellular matrix , genetically modified mouse , immunohistochemistry , pathology , beta catenin , matrix metalloproteinase , transgene , signal transduction , wnt signaling pathway , microbiology and biotechnology , chemistry , medicine , biology , anatomy , gene , biochemistry
Abstract Objective 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. Methods 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‐CreER T2 –transgenic mice were bred with β‐catenin fx(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. Results 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. Conclusion Our findings indicate that the β‐catenin signaling pathway plays a critical role in disc tissue function.