Transient anabolic effects accompany epidermal growth factor receptor signal activation in articular cartilage in vivo

Arthritis Research & Therapy

John B Shepard²  Jae-Wook Jeong³  Nita J Maihle¹  Sean O'Brien²  Caroline N Dealy⁴ 

[1] Departments of Obstetrics and Gynecology, Pathobiology, and Pharmacology, Yale University, 310 Cedar Street, New Haven, CT 06520, USA

[2] Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington CT 06030, USA

[3] Departments of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA

[4] Department of Orthopaedic Surgery, School of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA

关键词: Mig-6;    Cartilage repair;    Chondroprogenitors;    Progenitor cells;    Osteoarthritis;    Articular cartilage;    EGFR;    Epidermal growth factor receptor;   

Others  :  799225
DOI  :  10.1186/ar4233

 received in 2012-10-01, accepted in 2013-05-25,  发布年份 2013

【 摘 要 】

Introduction

Signals from the epidermal growth factor receptor (EGFR) have typically been considered to provide catabolic activities in articular cartilage, and accordingly have been suggested to have a causal role in osteoarthritis progression. The aim of this study was to determine in vivo roles for endogenous EGFR signal activation in articular cartilage.

Methods

Transgenic mice with conditional, limb-targeted deletion of the endogenous intracellular EGFR inhibitor Mig-6 were generated using CreLoxP (Mig-6-flox; Prx1Cre) recombination. Histology, histochemical staining and immunohistochemistry were used to confirm activation of EGFR signaling in the articular cartilage and joints, and to analyze phenotypic consequences of Mig-6 loss on articular cartilage morphology, proliferation, expression of progenitor cell markers, presence of chondrocyte hypertrophy and degradation of articular cartilage matrix.

Results

The articular cartilage of Mig-6-conditional knockout (Mig-6-cko) mice was dramatically and significantly thicker than normal articular cartilage at 6 and 12 weeks of age. Mig-6-cko articular cartilage contained a population of chondrocytes in which EGFR signaling was activated, and which were three to four times more proliferative than normal Mig-6-flox articular chondrocytes. These cells expressed high levels of the master chondrogenic regulatory factor Sox9, as well as high levels of putative progenitor cell markers including superficial zone protein (SZP), growth and differentiation factor-5 (GDF-5) and Notch1. Expression levels were also high for activated β-catenin and the transforming growth factor beta (TGF-β) mediators phospho-Smad2/3 (pSmad2/3). Anabolic effects of EGFR activation in articular cartilage were followed by catabolic events, including matrix degradation, as determined by accumulation of aggrecan cleavage fragments, and onset of hypertrophy as determined by type × collagen expression. By 16 weeks of age, the articular cartilage of Mig-6-cko knees was no longer thickened and was degenerating.

Conclusions

These results demonstrate unexpected anabolic effects of EGFR signal activation in articular cartilage, and suggest the hypothesis that these effects may promote the expansion and/or activity of an endogenous EGFR-responsive cell population within the articular cartilage.

【 授权许可】

   
2013 Shepard et al.; licensee BioMed Central Ltd.

【 图 表 】

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