In osteoarthritis (OA), interleukin-1 (IL-1) stimulates the expression of metalloproteinases and aggrecanases, which induce cartilage degradation. IL-1 is also capable of reducing the production of cartilage-specific macromolecules, including type II collagen, through modulation of the transcription factors Sp1 and Sp3. Conversely, Transforming growth factor-ß (TGF-β) counteracts with most of the IL-1 deleterious effects and contributes to cartilage homeostasis. However, OA chondrocytes progressively loose the expression of TGF-β type II receptor and become insensitive to the factor. This downregulation is also driven by IL-1. This review provides insights into the molecular mechanisms that underly the interplay between IL-1 and TGF-β in OA cartilage metabolism and enlightens the central role of Sp1 and Sp3 transcription factors in the matrix pathological alterations.

Although histone H3 lysine 27 trimethylation (H3K27Me3) is associated with gene silencing, whether H3K27Me3 demethylation affects transcription and cell differentiation in vivo has remained elusive. To investigate this, we conditionally inactivated the two H3K27Me3 demethylases, Jmjd3 and Utx, in non-dividing intrathymic CD4⁺ T-cell precursors. Here we show that both enzymes redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress. Thymocyte expression of S1pr1 was not rescued in Jmjd3- and Utx-deficient male mice, which carry the catalytically inactive Utx homolog Uty, supporting the conclusion that it requires H3K27Me3 demethylase activity. These findings demonstrate that Jmjd3 and Utx are required for T-cell development, and point to a requirement for their H3K27Me3 demethylase activity in cell differentiation.

Growing evidences indicate that the histone methyltransferase EZH2 (enhancer of zeste homolog 2) may be an appropriate therapeutic target in some tumors. Indeed, a high expression of EZH2 is correlated with poor prognosis and metastasis in many cancers. In addition, 3-Deazaneplanocin A (DZNep), an S-adenosyl-L homocysteine hydrolase inhibitor which induces EZH2 protein depletion, leads to cell death in several cancers and tumors. The aim of this study was to determine whether an epigenetic therapy targeting EZH2 with DZNep may be also efficient to treat chondrosarcomas. EZH2 expression was determined by immunohistochemistry and western-blot. Chondrosarcoma cell line CH2879 was cultured in the presence of DZNep, and its growth and survival were evaluated by counting adherent cells periodically. Apoptosis was assayed by cell cycle analysis, Apo2.7 expression using flow cytometry, and by PARP cleavage using western-blot. Cell migration was assessed by wound healing assay. Chondrosarcomas (at least with high grade) highly express EZH2, at contrary to enchondromas or chondrocytes. In vitro, DZNep inhibits EZH2 protein expression, and subsequently reduces the trimethylation of lysine 27 on histone H3 (H3K27me3). Interestingly, DZNep induces cell death of chondrosarcoma cell lines by apoptosis, while it slightly reduces growth of normal chondrocytes. In addition, DZNep reduces cell migration. These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treat chondrosarcomas.

Due to their low self-repair ability, cartilage defects that result from joint injury, aging, or osteoarthritis, are the most often irreversible and are a major cause of joint pain and chronic disability. So, in recent years, researchers and surgeons have been working hard to elaborate cartilage repair interventions for patients who suffer from cartilage damage. However, current methods do not perfectly restore hyaline cartilage and may lead to the apparition of fibro- or hypertrophic cartilage. In the next years, the development of new strategies using adult stem cells, in scaffolds, with supplementation of culture medium and/or culture in low oxygen tension should improve the quality of neoformed cartilage. Through these solutions, some of the latest technologies start to bring very promising results in repairing cartilage from traumatic injury or chondropathies. This review discusses the current knowledge about the use of adult stem cells in the context of cartilage tissue engineering and presents clinical trials in progress, as well as in the future, especially in the field of bioprinting stem cells.

Objective: Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin‐1β (IL‐1β) and transforming growth factor β1 (TGFβ1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL‐1β on TGFβ receptor type II (TGFβRII) regulation and TGFβ1 responsiveness in human articular chondrocytes.Methods: TGFβ1‐induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP‐Lux induction. Receptor‐activated Smad (R‐Smad) phosphorylation, TGFβ receptors, and Smad expression were determined by Western blotting and real‐time reverse transcription–polymerase chain reaction techniques. Signaling pathways were investigated using specific inhibitors, messenger RNA (mRNA) silencing, and expression vectors.Results: IL‐1β down‐regulated TGFβRII expression at both the protein and mRNA levels and led to inhibition of the TGFβ1‐induced gene expression and Smad2/3 phosphorylation. Moreover, IL‐1β strongly stimulated the expression of inhibitory Smad7. TGFβRII overexpression abolished the loss of TGFβ1 responsiveness induced by IL‐1β. The decrease in TGFβRII required de novo protein synthesis and involved both the NF‐κB and JNK pathways.Conclusion: We demonstrate that IL‐1β impairs TGFβ1 signaling through down‐regulation of TGFβRII, which is mediated by the p65/NF‐κB and activator protein 1/JNK pathways, and secondarily through the up‐regulation of Smad7. These findings show that there is cross‐talk in the signaling of 2 regulatory cytokines involved in inflammation.