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.
Highlights
Signals from the epidermal growth factor receptor (EGFR) have typically been considered to provide catabolic activities in articular cartilage, and have been suggested to have a causal role in osteoarthritis progression
Our study provides in vivo evidence for the involvement of EGFR signal activation in regulating potentially distinct anabolic and catabolic activities in articular cartilage, and demonstrates that the intracellular inhibitor Mig-6 normally functions to limit these activities
Release of Mig-6-mediated inhibition of EGFR signals leads to an initial, transient, thickening of the articular cartilage accompanied by proliferation and expansion of an EGFR-responsive cell population, which expresses high levels of the master chondrogenic regulatory factor Sox9, as well as high levels of other putative progenitor markers
Summary
Signals from the epidermal growth factor receptor (EGFR) have typically been considered to provide catabolic activities in articular cartilage, and have been suggested to have a causal role in osteoarthritis progression. A disadvantage of both of these approaches is that the defects tend to be filled by fibrocartilage [7], which lacks the durability of hyaline cartilage This is likely due to characteristics inherent in the repair cells, which include the poor proliferative capacity of adult or aged chondrocytes, and their tendency to de-differentiate [8]; and the cellular heterogeneity of bone marrow, which contains only a small percentage of progenitor cells capable of chondrogenic differentiation [9,10]. In vitro differentiation assays have demonstrated the potential of these cells to differentiate into the chondrogenic lineage [12,13,14,15,16,17,18], and the permanent hyaline or articular cartilage lineage [12,17,18] These populations have been suggested to represent a reserve capacity of the normal articular cartilage for homeostasis or regeneration [14,15,16]
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