T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling

Ma, Bin; Zhong, Leilei; Blitterswijk, Clemens A. van; Post, Janine N.; Karperien, Marcel

doi:10.1074/jbc.m113.453985

Cited by 61 publications

(46 citation statements)

References 35 publications

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“…We found that Osthole down-regulated β-catenin expression in a dose-dependent manner. We also detected the expression of down-stream molecules TCF4, which is deemed as a mediator Cellular Physiology and Biochemistry that contributes to cartilage degeneration though regulating the activity of the NF-κB pathway [42]. Protein expression levels of TCF4 were also decreased with Osthole treatment, which indicated that Wnt/β-catenin signaling was blocked by treatment of chondrocytes with Osthole.…”

Section: Discussionmentioning

confidence: 78%

Osthole Inhibits Proliferation and Induces Catabolism in Rat Chondrocytes and Cartilage Tissue

Song

Wei

et al. 2015

Cell Physiol Biochem

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Background/Aims: Cartilage destruction is thought to be the major mediator of osteoarthritis. Recent studies suggest that inhibition of subchrondral bone loss by anti-osteoporosis (OP) drug can protect cartilige erosion. Osthole, as a promising agent for treating osteoporosis, may show potential in treating osteoarthritis. The purpose of this study was to investigate whether Osthole affects the proliferation and catabolism of rat chondrocytes, and the degeneration of cartilage explants. Methods: Rat chondrocytes were treated with Osthole (0 μM, 6.25 μM, 12.5 μM, and 25 μM) with or without IL1-β (10ng/ml) for 24 hours. The expression levels of type II collagen and MMP13 were detected by western Blot. Marker genes for chondrocytes (A-can and Sox9), matrix metalloproteinases (MMPs), aggrecanases (ADAMTS5) and genes implicated in extracellular matrix catabolism were evaluated by qPCR. Cell proliferation was assessed by measuring proliferating cell nuclear antigen (PCNA) expression and fluorescence activated cell sorter. Wnt7b/β-catenin signaling was also investigated. Cartilage explants from two-week old SD rats were cultured with IL-1β, Osthole and Osthole plus IL-1β for four days and glycosaminoglycan (GAG) synthesis was assessed with toluidine blue staining and Safranine O/Fast Green FCF staining, collagen type II expression was detected by immunofuorescence. Results: Osthole reduced expression of chondrocyte markers and increased expression of MMP13, ADAMTS5 and MMP9 in a dose-dependent manner. Catabolic gene expression levels were further improved by Osthole plus IL-1β. Osthole inhibited chondrocyte proliferation. GAG synthesis and type II collagen were decreased in both the IL-1β groups and the Osthole groups, and significantly reduced by Osthole plus IL-1β. Conclusions: Our data suggested that Osthole increases the catabolism of rat chondrocytes and cartilage explants, this effect might be mediated through inhibiting Wnt7b/β-catenin pathway.

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Section: Discussionmentioning

confidence: 78%

Osthole Inhibits Proliferation and Induces Catabolism in Rat Chondrocytes and Cartilage Tissue

Song

Wei

et al. 2015

Cell Physiol Biochem

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“…However, function of Wnt pathway in chondrocyte homeostasis and OA pathogenesis remains controversial. For example, Transcription Factor 4 (TCF4), a downstream mediator of Wnt/β-catenin signaling was found elevated in human OA cartilage compared with healthy cartilage and may contribute to cartilage degeneration in OA [256]. In addition, TCF4 overexpression activated caspase 3/7 and induced human chondrocyte apoptosis (TUNEL measurement) [256].…”

Section: Cell Death Regulators In Chondrocytesmentioning

confidence: 99%

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Charlier

Relić

Deroyer

et al. 2016

IJMS

267

220

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Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression.

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“…For example, Axin2 shows less selectivity for specific TCF isoforms needed for WNT-induced transcription, whereas T/Bra is more stringent in its TCF-binding complement for WNT-induced transcription (48). Interestingly, full-length TCF4, but not LEF1 or TCF3, induces MMP1, MMP3, and MMP13 expression in human chondrocytes in vitro and is upregulated in human OA cartilage compared with healthy cartilage in vivo (49). This can be explained by increased TCF4-corepressor complexes forming due to the limited pool of β-catenin able to bind to TCF4, which overall promotes Mmp gene expression, similar to our results from overexpression of dnTCF4 in human chondrocytes.…”

Section: Ctnnb1mentioning

confidence: 99%

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis

Rockel

Whetstone

et al. 2016

Journal of Clinical Investigation

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T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling

Cited by 61 publications

References 35 publications

Osthole Inhibits Proliferation and Induces Catabolism in Rat Chondrocytes and Cartilage Tissue

Osthole Inhibits Proliferation and Induces Catabolism in Rat Chondrocytes and Cartilage Tissue

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis

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