Small molecule inhibitors of WNT/β-catenin signaling block IL-1β- and TNFα-induced cartilage degradation

Landman, Ellie; Miclea, Razvan L.; Blitterswijk, Clemens A. van; Karperien, Marcel

doi:10.1186/ar4273

Cited by 35 publications

(25 citation statements)

References 37 publications

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“…Interestingly, this effect could be partially alleviated by culturing the metatarsals in hypoxia and was more pronounced in the presence of O ‐phenanthroline (Figure C). We found, in accordance with previous studies (Landman et al , ), that the expression of matrix‐catabolic genes, such as Mmp13 and Mmp9 , was upregulated by treatment of the metatarsals with IL‐1 β and TNF α . Hypoxic culture conditions as well as O ‐phenanthroline downregulated the expression of both catabolic genes (Figure C).…”

Section: Resultssupporting

confidence: 93%

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O-Phenanthroline as modulator of the hypoxic and catabolic response in cartilage tissue-engineering models

Georgi

Landman

Blitterswijk

et al. 2014

J Tissue Eng Regen Med

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Hypoxia has been shown to be important for maintaining cartilage homeostasis as well as for inducing chondrogenic differentiation. Ensuring low oxygen levels during in vitro culture is difficult, therefore we assessed the chondro-inductive capabilities of the hypoxia-mimicking agent O-phenanthroline, which is also known as a non-specific matrix metalloproteinase (MMP) inhibitor. We found that O-phenanthroline reduced the expression of MMP3 and MMP13 mRNA levels during chondrogenic differentiation of human chondrocytes (hChs), as well as after TNFα/IL-1β exposure in an explant model. Interestingly, O-phenanthroline significantly inhibited matrix degradation in a TNFα/IL-1β-dependent model of cartilage degeneration when compared to control and natural hypoxia (2.5% O ). O-Phenanthroline had limited ability to improve the chondrogenic differentiation or matrix deposition in the chondrogenic pellet model. Additionally, O-phenanthroline alleviated MMP-induced cartilage degradation without affecting chondrogenesis in the explant culture. The data presented in this study indicate that the inhibitory effect of O-phenanthroline on MMP expression is dominant over the hypoxia-mimicking effect. Copyright © 2014 John Wiley & Sons, Ltd.

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Section: Resultssupporting

confidence: 93%

“…As shown previously, treatment with IL‐1 β and TNF α for 7 days potently induced cartilage matrix degradation in mouse fetal metatarsals (Landman et al , ). When cultured in hypoxic conditions, IL‐1 β ‐ and TNF α ‐induced cartilage degradation was reduced, as observed by light microscopy.…”

Section: Resultssupporting

confidence: 67%

O-Phenanthroline as modulator of the hypoxic and catabolic response in cartilage tissue-engineering models

Georgi

Landman

Blitterswijk

et al. 2014

J Tissue Eng Regen Med

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“…Because age is a major risk factor for arthritis, we evaluated mouse metatarsal bones from two different ages, one of early adulthood (10 weeks old) in the mouse and one of later adulthood (29 weeks old). We opted to culture metatarsal bones for their ease of organ culture and susceptibility to inflammation-mediated arthritic damage in culture [47–50]. …”

Section: Resultsmentioning

confidence: 99%

Pigment Epithelium-Derived Factor (PEDF) mediates cartilage matrix loss in an age-dependent manner under inflammatory conditions

Nakamura

Hollander

Uchimura

et al. 2017

BMC Musculoskelet Disord

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BackgroundInflammation is a major cause of cartilage destruction and leads to the imbalance of metabolic activities in the arthritic joint. Pigment epithelium-derived factor (PEDF) has been reported to have both pro- and anti-inflammatory activities in various cell types and to be upregulated in the arthritic joint, but its role in joint destruction is unclear. Our aim was to investigate the role of PEDF in cartilage degeneration under inflammatory conditions.MethodsPEDF was ectopically expressed in primary human articular chondrocytes, and catabolic gene expression and protein secretion in response to the pro-inflammatory cytokine interleukin 1 beta (IL-1β) were evaluated. Metatarsal bones from PEDF-deficient and wild type mice were cultured in the presence or absence of IL-1β. Cartilage matrix integrity and matrix metalloproteinases MMP-1, MMP-3, and MMP-13 were evaluated. PEDF-deficient and wild type mice were evaluated in the monosodium iodoacetate (MIA) inflammatory joint destruction animal model to determine the role of PEDF in inflammatory arthritis in vivo. Student’s t-tests and Mann–Whitney tests were employed where appropriate, for parametric and non-parametric data, respectively.ResultsWe showed that PEDF protein levels were higher in human osteoarthritis samples compared to normal samples. We demonstrated that ectopic PEDF expression in primary human articular chondrocytes exacerbated catabolic gene expression in the presence of IL-1β. In whole bone organ cultures, IL-1β induced MMP-1, MMP-3 and MMP-13 protein production, and caused significant cartilage matrix loss. Interestingly, Toluidine Blue staining showed that PEDF-deficient bones from 29 week old animals, but not 10 week old animals, had reduced matrix loss in response to IL-1β compared to their wild type counterparts. In addition, PEDF-deficiency in 29 week old animals preserved matrix integrity and protected against cell loss in the MIA joint destruction model in vivo.ConclusionWe conclude that PEDF exacerbates cartilage degeneration in an age-dependent manner under an inflammatory setting. This is the first study identifying a specific role for PEDF in joint inflammation and highlights the multi-faceted activities of PEDF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-017-1410-y) contains supplementary material, which is available to authorized users.

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“…Interleukin‐1β (IL‐1β), when used as a potent inflammatory cytokine, has been linked to delaying the fracture healing process, as well as the process of severe bone loss, and the overexpression of fracture cells (Hengartner, Fiedler, Ignatius, & Brenner, ; Lange et al, ). Interestingly, inhibition of the Wnt/β‐catenin signaling pathway could inhibit IL‐1β‐ and tumor necrosis factor‐α‐induced cartilage degradation by suppressing expression of matrix metalloproteinase (MMP; Landman, Miclea, van Blitterswijk, & Karperien, ). The activation of the Wnt/β‐catenin signaling pathway has been associated with inducing the proliferation of adipose‐derived stem cells and osteogenic differentiation (Shao et al, ).…”

Section: Introductionmentioning

confidence: 99%

Retracted: Long noncoding RNA ZBED3‐AS1 induces the differentiation of mesenchymal stem cells and enhances bone regeneration by repressing IL‐1β via Wnt/β‐catenin signaling pathway

Jiang

Sun

et al. 2019

Journal Cellular Physiology

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Bone regeneration, as a physiological process of bone formation, is regulated by multiple cytokines. Long noncoding RNAs are involved in the progress of bone formation. The present study investigated role by which ZBED3‐AS1 acts to control the differentiation of mesenchymal stem cells (MSCs) and bone regeneration. Bioinformatics prediction and dual luciferase reporter gene assay identified putative ZBED3‐AS1 binding sites on the 3′‐untranslated region of interleukin‐1β (IL‐1β). Then, RNA immunoprecipitation and chromatin immunoprecipitation assays confirmed that ZBED3‐AS1 could regulate the expression of IL‐1β by binding to the transcription factor CREB. Notably, ZBED3‐AS1 was shown to negatively regulate IL‐1β expression. After model establishment in rats simulating bone injury, MSCs were isolated and delivered with ZBED3‐AS1, Si‐ZBED3‐AS1, Si‐IL‐1β, or DKK (inhibitor of Wnt/β‐catenin signaling pathway) to identify their roles in osteogenic differentiation by evaluating MSC colony formation and proliferation. Then, number of mineralized nodules, alkaline phosphatase (ALP) activity and osteocalcin (OCN) expression, and expression of osteogenesis‐related genes were determined. Overexpression of ZBED3‐AS1 or silencing of IL‐1β was shown to accelerate ectopic osteogenesis, as reflected by increasing the number of mineralized nodules, ALP activity, and OCN expression, and promoting MSC colony formation and proliferation. Additionally, ZBED3‐AS1 activated the Wnt/β‐catenin signaling pathway by negatively regulating IL‐1β. IL‐1β inhibited osteogenic differentiation by suppressing the Wnt/β‐catenin signaling pathway. Furthermore, the effect of ZBED3‐AS1 and IL‐1β on osteogenic differentiation was confirmed in vivo. Taken together, upregulation of ZBED3‐AS1 could restore differentiation of MSCs and enhance bone regeneration via activation of Wnt/β‐catenin signaling pathway by repressing IL‐1β.

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Small molecule inhibitors of WNT/β-catenin signaling block IL-1β- and TNFα-induced cartilage degradation

Cited by 35 publications

References 37 publications

O-Phenanthroline as modulator of the hypoxic and catabolic response in cartilage tissue-engineering models

O-Phenanthroline as modulator of the hypoxic and catabolic response in cartilage tissue-engineering models

Pigment Epithelium-Derived Factor (PEDF) mediates cartilage matrix loss in an age-dependent manner under inflammatory conditions

Retracted: Long noncoding RNA ZBED3‐AS1 induces the differentiation of mesenchymal stem cells and enhances bone regeneration by repressing IL‐1β via Wnt/β‐catenin signaling pathway

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