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Articular Chondrocytes

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Martin Lotz – 1st expert on this subject based on the ideXlab platform

  • exosomes from il 1β stimulated synovial fibroblasts induce osteoarthritic changes in Articular Chondrocytes
    Arthritis Research & Therapy, 2014
    Co-Authors: Tomohiro Kato, Martin Lotz, Shigeru Miyaki, Hiroyuki Ishitobi, Yoshihiro Nakamura, Tomoyuki Nakasa, Mitsuo Ochi

    Abstract:

    Osteoarthritis (OA) is a whole joint disease, and characterized by progressive degradation of Articular cartilage, synovial hyperplasia, bone remodeling and angiogenesis in various joint tissues. Exosomes are a type of microvesicles (MVs) that may play a role in tissue-tissue and cell-cell communication in homeostasis and diseases. We hypothesized that exosomes function in a novel regulatory network that contributes to OA pathogenesis and examined the function of exosomes in communication among joint tissue cells. Human synovial fibroblasts (SFB) and Articular Chondrocytes were obtained from normal knee joints. Exosomes isolated from conditioned medium of SFB were analyzed for size, numbers, markers and function. Normal Articular Chondrocytes were treated with exosomes from SFB, and Interleukin-1β (IL-1β) stimulated SFB. OA-related genes expression was quantified using real-time PCR. To analyze exosome effects on cartilage tissue, we performed glycosaminoglycan release assay. Angiogenic activity of these exosomes was tested in migration and tube formation assays. Cytokines and miRNAs in exosomes were analyzed by Bio-Plex multiplex assay and NanoString analysis. Exosomes from IL-1β stimulated SFB significantly up-regulated MMP-13 and ADAMTS-5 expression in Articular Chondrocytes, and down-regulated COL2A1 and ACAN compared with SFB derived exosomes. Migration and tube formation activity were significantly higher in human umbilical vein endothelial cells (HUVECs) treated with the exosomes from IL-1β stimulated SFB, which also induced significantly more proteoglycan release from cartilage explants. Inflammatory cytokines, IL-6, MMP-3 and VEGF in exosomes were only detectable at low level. IL-1β, TNFα MMP-9 and MMP-13 were not detectable in exosomes. NanoString analysis showed that levels of 50 miRNAs were differentially expressed in exosomes from IL-1β stimulated SFB compared to non-stimulated SFB. Exosomes from IL-1β stimulated SFB induce OA-like changes both in vitro and in ex vivo models. Exosomes represent a novel mechanism by which pathogenic signals are communicated among different cell types in OA-affected joints.

  • chemotaxis of human Articular Chondrocytes and mesenchymal stem cells
    Journal of Orthopaedic Research, 2008
    Co-Authors: Yasunori Mishima, Martin Lotz

    Abstract:

    Migration of Chondrocytes and mesenchymal stem cells (MSCs) may be important in cartilage development, tissue response to injury, and in tissue engineering. This study analyzed growth factors and cytokines for their ability to induce migration of human Articular Chondrocytes and bone marrow-derived mesenchymal stem cells in Boyden chamber assays.In human Articular Chondrocytes serum induced dose- and time-dependent increases in cell migration. Among a series of growth factors and cytokines tested only PDGF induced a significant increase in cell migration. The PDGF isoforms AB and BB were more potent than AA. There was an aging-related decline in the ability of Chondrocytes to migrate in response to serum and PDGF. Human bone marrow MSC showed significant chemotaxis responses to several factors, including FBS, PDGF, VEGF, IGF-1, IL-8, BMP-4, and BMP-7. In summary, these results demonstrate that directed cell migration is inducible in human Articular Chondrocytes and MSC. PDGF is the most potent factor analyzed, and may be useful to promote tissue integration during cartilage repair or tissue engineering. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1407–1412, 2008

  • il 18 is produced by Articular Chondrocytes and induces proinflammatory and catabolic responses
    Journal of Immunology, 1999
    Co-Authors: Tsaiwei Olee, Sanshiro Hashimoto, Jacqueline Quach, Martin Lotz

    Abstract:

    IL-18, a cytokine originally identified as IFN-γ-inducing factor, is a member of the IL-1 family of proteins. Because IL-1α and IL-1β are important mediators in the pathogenesis of arthritis, the present study addresses the expression of IL-18 and its role in regulating in Articular Chondrocytes. IL-18 mRNA was induced by IL-1β in Chondrocytes. Chondrocytes produced the IL-18 precursor and in response to IL-1 stimulation secreted the mature form of IL-18. Studies on IL-18 effects on Chondrocytes showed that it inhibits TGF-β-induced proliferation and enhances nitric oxide production. IL-18 stimulated the expression of several genes in normal human Articular Chondrocytes including inducible nitric oxide synthase, inducible cyclooxygenase, IL-6, and stromelysin. Gene expression was associated with the synthesis of the corresponding proteins. Treatment of normal human Articular cartilage with IL-18 increased the release of glycosaminoglycans. These finding identify IL-18 as a cytokine that regulates chondrocyte responses and contributes to cartilage degradation.

Di Chen – 2nd expert on this subject based on the ideXlab platform

  • fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2 induced catabolic activities in human Articular Chondrocytes
    Arthritis Research & Therapy, 2011
    Co-Authors: Di Chen, Heejeong Im, Simon M Cool, Andre J Van Wijnen, Katalin Mikecz, Gillian Murphy

    Abstract:

    Introduction: Cartilage degeneration driven by catabolic stimuli is a critical pathophysiological process in osteoarthritis (OA). We have defined fibroblast growth factor 2 (FGF-2) as a degenerative mediator in adult human Articular Chondrocytes. Biological effects mediated by FGF-2 include inhibition of proteoglycan production, upregulation of matrix metalloproteinase-13 (MMP-13), and stimulation of other catabolic factors. In this study, we identified the specific receptor responsible for the catabolic functions of FGF-2, and established a pathophysiological connection between the FGF-2 receptor and OA. Methods: Primary human Articular Chondrocytes were cultured in monolayer (24 hours) or alginate beads (21 days), and stimulated with FGF-2 or FGF18, in the presence or absence of FGFR1 (FGF receptor 1) inhibitor. Proteoglycan accumulation and chondrocyte proliferation were assessed by dimethylmethylene blue (DMMB) assay and DNA assay, respectively. Expression of FGFRs (FGFR1 to FGFR4) was assessed by flow cytometry, immunoblotting, and quantitative real-time PCR (qPCR). The distinctive roles of FGFR1 and FGFR3 after stimulation with FGF-2 were evaluated using either pharmacological inhibitors or FGFR small interfering RNA (siRNA). Luciferase reporter gene assays were used to quantify the effects of FGF-2 and FGFR1 inhibitor on MMP-13 promoter activity. Results: Chondrocyte proliferation was significantly enhanced in the presence of FGF-2 stimulation, which was inhibited by the pharmacological inhibitor of FGFR1. Proteoglycan accumulation was reduced by 50% in the presence of FGF-2, and this reduction was successfully rescued by FGFR1 inhibitor. FGFR1 inhibitors also fully reversed the up-regulation of MMP-13 expression and promoter activity stimulated by FGF-2. Blockade of FGFR1 signaling by either chemical inhibitors or siRNA targeting FGFR1 rather than FGFR3 abrogated the up-regulation of matrix metalloproteinases 13 (MMP-13) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 5 (ADAMTS5), as well as down-regulation of aggrecan after FGF-2 stimulation. Flow cytometry, qPCR and immunoblotting analyses suggested that FGFR1 and FGFR3 were the major FGFR isoforms expressed in human Articular Chondrocytes. FGFR1 was activated more potently than FGFR3 upon FGF-2 stimulation. In osteoarthritic Chondrocytes, FGFR3 was significantly down regulated (P < 0.05) with a concomitant increase in the FGFR1 to FGFR3 expression ratio (P < 0.05), compared to normal Chondrocytes. Our results also demonstrate that FGFR3 was negatively regulated by FGF-2 at the transcriptional level through the FGFR1-ERK (extracellular signal-regulated kinase) signaling pathway in human Articular Chondrocytes.

  • inhibition of β catenin signaling in Articular Chondrocytes results in Articular cartilage destruction
    Arthritis & Rheumatism, 2008
    Co-Authors: Mo Chen, Michael J Zuscik, Qiuqian Wu, Yong Jun Wang, Randy N Rosier, Regis J Okeefe, Di Chen

    Abstract:

    Osteoarthritis (OA) is a degenerative joint disease. Numerous genetic and environmental factors have been proposed as contributors to the development of OA. The progression of the disease is slow and eventually results in degeneration and loss of the Articular cartilage in various joints, including fingers, knees, hips, and spine. The disease process leads to limitation of joint movement, joint deformity, joint stiffness, inflammation, and severe pain. The mechanism of OA pathogenesis remains undefined.

    OA is mediated by a dynamic interplay between the Articular Chondrocytes, their matrix, and synovial cells. Articular Chondrocytes, the cell type present in Articular cartilage, are responsible for producing and maintaining the extracellular matrix (ECM), which supports the appropriate biomechanical function of the tissue. Phenotypic changes seen in OA are often accompanied by ECM degradation, which eventually results in cartilage destruction (1). Synovial fibroblasts are mesenchyme-derived cells that form a thin lining of synovial tissue surrounding the fibrous capsule of the joint. The physiologic roles of synovial tissue are to produce synovial fluid that lubricates the joints and to supply nutrients to the Articular Chondrocytes.

    Articular cartilage plays a crucial role in joint function during adulthood, and destruction of Articular cartilage has severe consequences. While most cartilages are replaced by bone during development, only a few cartilages are permanent, including Articular cartilage. Articular Chondrocytes, which function to maintain the matrix, are unique among growth plate Chondrocytes in that they exhibit very limited mitotic activity, have a slow rate of matrix synthesis and degradation, and do not progress fully to the terminally differentiated phenotype displayed by cells in the growth plate (2). Very little is known regarding the mechanisms involved in establishing and maintaining this Articular chondrocyte phenotype.

    The function of Articular Chondrocytes is regulated by a variety of growth factors, including Wnt/β-catenin signaling molecules, which play a critical role in chondrocyte proliferation, differentiation, and apoptosis. Beta-catenin is a key molecule in the canonical Wnt signaling pathway and plays a critical role in multiple steps during chondrocyte formation and maturation (3,4). Inhibitor of β-catenin and T cell factor (ICAT) is an 82-amino-acid small molecule (5) whose crystal structure reveals binding capacity to the armadillo repeats of β-catenin. This binding disrupts the complex formation of β-catenin with T cell factor (TCF)/lymphoid enhancer factor (LEF) (6,7) and thus leads to inhibition of signaling in this pathway. To investigate the role of β-catenin signaling in the maintenance of Articular cartilage function under physiologic and pathophysiologic conditions, we generated Col2a1-ICAT–transgenic mice in which the ICAT transgene was targeted specifically to Chondrocytes using the Col2a1 promoter. We found that the ICAT transgene was highly expressed in Articular Chondrocytes in 6-month-old transgenic mice, leading to inhibition of β-catenin signaling in transgenic mouse Chondrocytes. Associated with this, severe Articular cartilage destruction was observed in Col2a1-ICAT–transgenic mice. Articular chondrocyte apoptosis was significantly increased, providing novel evidence regarding the contribution of β-catenin signaling to the maintenance of normal Articular cartilage function.

  • Tamoxifen-Inducible Cre-Recombination in Articular Chondrocytes of Adult Col2a1-CreERT2 Transgenic Mice
    Osteoarthritis and Cartilage, 2007
    Co-Authors: Mo Chen, Alexander C. Lichtler, Regis J. O'keefe, Di Chen

    Abstract:

    Summary Objective To determine the specificity and efficiency of the tamoxifen (TM)-induced Cre-recombination in Articular Chondrocytes of adult Col2a1-CreER T2 transgenic mice. Methods Col2a1-CreER T2 transgenic mice were bred with Rosa26 reporter mice. Two-week-old Col2a1-CreER T2 ;R26R mice were administered TM for 5 days and were sacrificed 1 and 6 months after TM induction. X-Gal staining was performed. Results Efficient Cre-recombination is achieved in adult Articular Chondrocytes 1 and 6 months after TM induction. Conclusion Our findings demonstrate that the Col2a1-CreER T2 transgenic mouse model is a valuable tool to target genes specifically expressed in Articular Chondrocytes in a temporally controlled manner in adult mice.

Heejeong Im – 3rd expert on this subject based on the ideXlab platform

  • fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2 induced catabolic activities in human Articular Chondrocytes
    Arthritis Research & Therapy, 2011
    Co-Authors: Di Chen, Heejeong Im, Simon M Cool, Andre J Van Wijnen, Katalin Mikecz, Gillian Murphy

    Abstract:

    Introduction: Cartilage degeneration driven by catabolic stimuli is a critical pathophysiological process in osteoarthritis (OA). We have defined fibroblast growth factor 2 (FGF-2) as a degenerative mediator in adult human Articular Chondrocytes. Biological effects mediated by FGF-2 include inhibition of proteoglycan production, upregulation of matrix metalloproteinase-13 (MMP-13), and stimulation of other catabolic factors. In this study, we identified the specific receptor responsible for the catabolic functions of FGF-2, and established a pathophysiological connection between the FGF-2 receptor and OA. Methods: Primary human Articular Chondrocytes were cultured in monolayer (24 hours) or alginate beads (21 days), and stimulated with FGF-2 or FGF18, in the presence or absence of FGFR1 (FGF receptor 1) inhibitor. Proteoglycan accumulation and chondrocyte proliferation were assessed by dimethylmethylene blue (DMMB) assay and DNA assay, respectively. Expression of FGFRs (FGFR1 to FGFR4) was assessed by flow cytometry, immunoblotting, and quantitative real-time PCR (qPCR). The distinctive roles of FGFR1 and FGFR3 after stimulation with FGF-2 were evaluated using either pharmacological inhibitors or FGFR small interfering RNA (siRNA). Luciferase reporter gene assays were used to quantify the effects of FGF-2 and FGFR1 inhibitor on MMP-13 promoter activity. Results: Chondrocyte proliferation was significantly enhanced in the presence of FGF-2 stimulation, which was inhibited by the pharmacological inhibitor of FGFR1. Proteoglycan accumulation was reduced by 50% in the presence of FGF-2, and this reduction was successfully rescued by FGFR1 inhibitor. FGFR1 inhibitors also fully reversed the up-regulation of MMP-13 expression and promoter activity stimulated by FGF-2. Blockade of FGFR1 signaling by either chemical inhibitors or siRNA targeting FGFR1 rather than FGFR3 abrogated the up-regulation of matrix metalloproteinases 13 (MMP-13) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 5 (ADAMTS5), as well as down-regulation of aggrecan after FGF-2 stimulation. Flow cytometry, qPCR and immunoblotting analyses suggested that FGFR1 and FGFR3 were the major FGFR isoforms expressed in human Articular Chondrocytes. FGFR1 was activated more potently than FGFR3 upon FGF-2 stimulation. In osteoarthritic Chondrocytes, FGFR3 was significantly down regulated (P < 0.05) with a concomitant increase in the FGFR1 to FGFR3 expression ratio (P < 0.05), compared to normal Chondrocytes. Our results also demonstrate that FGFR3 was negatively regulated by FGF-2 at the transcriptional level through the FGFR1-ERK (extracellular signal-regulated kinase) signaling pathway in human Articular Chondrocytes.