Hepatocyte growth factor/scatter factor is not a potent regulator of anabolic and catabolic gene expression in adult human articular chondrocytes

Bau, Brigitte; McKenna, Louise A.; Söeder, Stephan; Fan, Zhiyong; Pecht, Anja; Aigner, Thomas

doi:10.1016/j.bbrc.2004.03.001

Cited by 17 publications

(15 citation statements)

References 18 publications

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“…In addition, Mig-6 can directly bind to and inhibit signal transduction by the EGFR-related receptor, ErbB2 [66]. Some EGFR-independent effects of Mig-6 have been reported including direct inhibition of ERK [67] and hepatocyte growth factor (HGF)/Met signaling [68]; however, HGF is not a potent regulator of anabolic or catabolic gene expression in articular chondrocytes [69]. Our observation that EGFR signaling is dramatically increased in Mig-6 -cko articular cartilage in the same regions where we observe major phenotypic effects is consistent with a potentially primary role for the EGFR in mediating most, if not all, of the articular cartilage responses we have observed.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…IGF-1 can stimulate chondrocyte synthesis of ECM in a dose dependent manner[5-10]. While culture conditions have varied, (e.g., explants, cell-seeded gels, cell monolayers), chondrocyte biosynthesis levels increased from 1.5- [8] to 2-6 fold over[7,10-12] control levels. IGF-1 can also inhibit production of specific proteins such as MMP-13[13].…”

Section: Introductionmentioning

confidence: 99%

“…At the gene expression level, type II collagen was significantly up-regulated by IGF-1[7,14-16]. Aggrecan transcripts showed no[7,8] or slight up-regulation by 48 hours of IGF-1 treatment[16], though moderate up-regulation (130%) after 1-3 weeks[14]. The transcription factor, Sox-9, also showed no significant response to IGF-1[15].…”

Section: Introductionmentioning

confidence: 99%

IGF-1 does not moderate the time-dependent transcriptional patterns of key homeostatic genes induced by sustained compression of bovine cartilage

Wheeler

Jafarzadeh

Rocke

et al. 2009

Osteoarthritis and Cartilage

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Objective To determine changes in chondrocyte transcription of a range of anabolic, catabolic and signaling genes following simultaneous treatment of cartilage with IGF-1 and ramp-and-hold mechanical compression, and compare with effects on biosynthesis. Methods Explant disks of bovine calf cartilage were slowly compressed (unconfined) over 3-min to their 1mm cut-thickness (0%-compression) or to 50%-compression with or without 300 ng/ml IGF-1. Expression of 24 genes involved in cartilage homeostasis was measured using qPCR at 2, 8, 24, 32, 48 hours after compression ± IGF-1. Clustering analysis was used to identify groups of co-expressed genes to further elucidate mechanistic pathways. Results IGF-1 alone stimulated gene expression of aggrecan and collagen II, but simultaneous 24-hour compression suppressed this effect. Compression alone upregulated expression of MMP-3, MMP-13, ADAMTS-5 and TGF-β, an effect not reversed by simultaneous IGF-1 treatment. Temporal changes in expression following IGF-1 treatment were generally slower than that following compression. Clustering analysis revealed five distinct groups within which the pairings, TIMP-3 and ADAMTS-5, MMP-1 and IGF-2, and IGF-1 and Collagen II, were all robustly co-expressed, suggesting inherent regulation and feedback in chondrocyte gene expression. While aggrecan synthesis was transcriptionally regulated by IGF-1, inhibition of aggrecan synthesis by sustained compression appeared post-transcriptionally regulated. Conclusion Sustained compression markedly altered the effects of IGF-1 on expression of genes involved in cartilage homeostasis, while IGF-1 was largely unable to moderate the transcriptional effects of compression alone. The demonstrated co-expressed gene pairings suggest a balance of anabolic and catabolic activity following simultaneous mechanical and growth factor stimuli.

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“…This regulatory role is modulated by speci ic signalling molecules such as TGF-β1 and hepatocyte growth factor (HGF). Hence, it is important to remember the key role played by cytokines and growth factors in osteophyte formation, the elevation of TGF-β1 41 and HGF levels in OA cartilage 42,43 , and elevated messenger RNA (mRNA) and protein levels of both TGF-β1 41,44 and HGF 42 in OA osteoblasts. MSC isolated from adipose tissue secrete HGF that can decrease TGF-β1 production in co-cultures with chondrocytes, indicating another potential crosstalk between different joint tissues 45 .…”

Section: Role Of Mscs In Oamentioning

confidence: 99%

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2013

OA Arthritis

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Hepatocyte growth factor/scatter factor is not a potent regulator of anabolic and catabolic gene expression in adult human articular chondrocytes

Cited by 17 publications

References 18 publications

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

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

IGF-1 does not moderate the time-dependent transcriptional patterns of key homeostatic genes induced by sustained compression of bovine cartilage

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