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Arthritis Research and Therapy

, 15:R60

First Online: 25 May 2013Received: 01 October 2012Revised: 17 February 2013Accepted: 25 May 2013

Abstract

IntroductionSignals 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.

MethodsTransgenic 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.

ResultsThe 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.

ConclusionsThese 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.

KeywordsEpidermal growth factor receptor EGFR Articular cartilage Osteoarthritis Progenitor cells Chondroprogenitors Cartilage repair Mig-6 AbbreviationsEGFepidermal growth factor

EGFRepidermal growth factor receptor

GDF-5growth and differentiation-5

HGFhepatocyte growth factor

HB-EGFheparin-binding epidermal growth factor

Mig-6-cko Mig-6conditional knock out

pSmad2-3phospho-Smad2-3

SZPsuperficial zone protein

TGF-αtransforming growth factor alpha

TGF-βtransforming growth factor beta

Electronic supplementary materialThe online version of this article doi:10.1186-ar4233 contains supplementary material, which is available to authorized users.

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Autor: John B Shepard - Jae-Wook Jeong - Nita J Maihle - Sean O-Brien - Caroline N Dealy

Fuente: https://link.springer.com/







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