Objective. Autologous chondrocyte implantation requires expansion of cells ex vivo, leading to dedifferentiation of chondrocytes (loss of aggrecan and type II collagen to the profit of type I and type III collagens). Several approaches have been described for redifferentiation of these cells. Among them, low oxygen tension has been exploited to restore the differentiated chondrocyte phenotype, but molecular mechanisms of this process remain unclear. However, under conditions of hypoxia, one of the major factors involved is hypoxiainducible factor 1␣ (HIF-1␣). The purpose of this study was to investigate the role of HIF-1␣ during human chondrocyte redifferentiation.Methods. We used complementary approaches to achieving HIF-1␣ loss (inhibition by cadmium ions and dominant-negative expression) or gain (ectopic expression and cobalt ion treatment) of function. Expression of chondrocyte, as well as fibroblast-like, phenotype markers was determined using real-time reverse transcription-polymerase chain reaction and Western blot analyses. Binding activities of HIF-1␣ and SOX9, a pivotal transcription factor of chondrogenesis, were evaluated by electrophoretic mobility shift assays and by chromatin immunoprecipitation assay.Results. We found that hypoxia and HIF-1␣ not only induced the expression of SOX9, COL2A1, and aggrecan, but they simultaneously inhibited the expression of COL1A1, COL1A2, and COL3A1. In addition, we identified the binding of HIF-1␣ to the aggrecan promoter, the first such reported demonstration of this binding.Conclusion. This study is the first to show a bimodal role of HIF-1␣ in cartilage homeostasis, since HIF-1␣ was shown to favor specific markers and to impair dedifferentiation. This suggests that manipulation of HIF-1␣ could represent a promising approach to the treatment of osteoarthritis.
Objective. Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1 (IL-1) and transforming growth factor 1 (TGF1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1 on TGF receptor type II (TGFRII) regulation and TGF1 responsiveness in human articular chondrocytes.Methods. TGF1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (RSmad) phosphorylation, TGF 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-1 down-regulated TGFRII expression at both the protein and mRNA levels and led to inhibition of the TGF1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1 strongly stimulated the expression of inhibitory Smad7.TGFRII overexpression abolished the loss of TGF1 responsiveness induced by IL-1. The decrease in TGFRII required de novo protein synthesis and involved both the NF-B and JNK pathways.Conclusion. We demonstrate that IL-1 impairs TGF1 signaling through down-regulation of TGFRII, which is mediated by the p65/NF-B 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.
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.
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