BMP-2-enhanced chondrogenesis involves p38 MAPK-mediated down-regulation of Wnt-7a pathway

Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Korea.
Molecules and Cells (Impact Factor: 2.09). 01/2007; 22(3):353-9.
Source: PubMed

ABSTRACT The bone morphogenetic protein (BMP) family has been implicated in control of cartilage development. Here, we demonstrate that BMP-2 promotes chondrogenesis by activating p38 mitogen-activated protein kinase (MAPK), which in turn downregulates Wnt-7a/b-catenin signaling responsible for proteasomal degradation of Sox9. Exposure of mesenchymal cells to BMP-2 resulted in upregulation of Sox9 protein and a concomitant decrease in the level of b-catenin protein and Wnt-7a signaling. In agreement with this, the interaction of Sox9 with b-catenin was inhibited in the presence of BMP-2. Inhibition of the p38 MAPK pathway using a dominant negative mutant led to sustained Wnt-7a signaling and decreased Sox9 expression, with consequent inhibition of precartilage condensation and chondrogenic differentiation. Moreover, overexpression of b-catenin caused degradation of Sox9 via the ubiquitin/26S proteasome pathway. Our results collectively indicate that the increase in Sox9 protein resulting from downregulation of b-catenin/Wnt-7a signaling is mediated by p38 MAPK during BMP-2 induced chondrogenesis in chick wing bud mesenchymal cells.

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Available from: Shin-Sung Kang, Jul 21, 2014
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    • "Comparatively, the inhibition of PKCα or p38 MAPK activity abolishes the promotion of chondrogenic differentiation by overexpressing Wnt5a or exogenous TGFβ3. On the other hand, the partial reduction of endogenous WNT5A by small interfering RNA diminishes TGFβ3-stimulated chondrogenesis through the inhibition of PKCα and p38 MAPK activity (Jin et al. 2006a). Wnt5a has also been found to promote ERK1/2 phosphorylation in endothelial cells (Masckauchán et al. 2006); the expression of Wnt5a blocks canonical Wnt signaling in endothelial cells and other cell types (Topol et al. 2003) (Fig. 4). "
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    ABSTRACT: Chondrogenesis is a developmental process that is controlled and coordinated by many growth and differentiation factors, in addition to environmental factors that initiate or suppress cellular signaling pathways and the transcription of specific genes in a temporal-spatial manner. As key signaling molecules in regulating cell proliferation, homeostasis and development, both mitogen-activated protein kinases (MAPK) and the Wnt family participate in morphogenesis and tissue patterning, playing important roles in skeletal development, especially chondrogenesis. Recent findings suggest that both signals are also actively involved in arthritis and related diseases. Despite the implication that crosstalk between MAPK and Wnt signaling has a significant function in cancer, few studies have summarized this interaction and its regulation of chondrogenesis. In this review, we focus on MAPK and Wnt signaling, referencing their relationships in various types of cells and particularly to their influence on chondrogenesis and cartilage development. We also discuss the interactions between MAPK and Wnt signaling with respect to cartilage-related diseases such as osteoarthritis and explore potential therapeutic targets for disease treatments.
    Cell and Tissue Research 10/2014; 358(3). DOI:10.1007/s00441-014-2010-x · 3.57 Impact Factor
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    • "Regulation of lineage-specific genes is crucial in this temporal process, [21]. Transforming growth factor (TGF)-beta1 is essential for induction of chondrocyte differentiation of hMSC, a process which is strongly enhanced by the additional presence of bone morphogenetic protein (BMP)2, [22] and [23]. In this section, we describe the complementary effects of TGF-beta1 and BMP2 by multi-stimuli multi-experiment inference applying the NetGenerator algorithm. "
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    ABSTRACT: Background Inference of gene-regulatory networks (GRNs) is important for understanding behaviour and potential treatment of biological systems. Knowledge about GRNs gained from transcriptome analysis can be increased by multiple experiments and/or multiple stimuli. Since GRNs are complex and dynamical, appropriate methods and algorithms are needed for constructing models describing these dynamics. Algorithms based on heuristic approaches reduce the effort in parameter identification and computation time. Results The NetGenerator V2.0 algorithm, a heuristic for network inference, is proposed and described. It automatically generates a system of differential equations modelling structure and dynamics of the network based on time-resolved gene expression data. In contrast to a previous version, the inference considers multi-stimuli multi-experiment data and contains different methods for integrating prior knowledge. The resulting significant changes in the algorithmic procedures are explained in detail. NetGenerator is applied to relevant benchmark examples evaluating the inference for data from experiments with different stimuli. Also, the underlying GRN of chondrogenic differentiation, a real-world multi-stimulus problem, is inferred and analysed. Conclusions NetGenerator is able to determine the structure and parameters of GRNs and their dynamics. The new features of the algorithm extend the range of possible experimental set-ups, results and biological interpretations. Based upon benchmarks, the algorithm provides good results in terms of specificity, sensitivity, efficiency and model fit.
    BMC Systems Biology 01/2013; 7(1):1. DOI:10.1186/1752-0509-7-1 · 2.44 Impact Factor
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    • "Previously, our laboratory demonstrated that down-regulation of interaction between fibronectin and integrin b1 by the activation of MMP-2 resulted in a decreased condensation of chick limb mesenchymal cells (Jin et al., 2006). The expression of integrin b1 protein was increased at an early time and then decreased as chondrocyte differentiation occurs. "
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    ABSTRACT: miRNAs (microRNAs) have proven to play essential roles in diverse biological processes including early development, cell proliferation and cell death, and cell differentiation. However, there is only limited amount of information about their potential role in chondrogenesis. In the present study, we investigated the role of miRNA-488 in the cellular condensation, which is essential initiation for chondrogenic differentiation. We found that miRNA-488 expression is up-regulated at the precondensation stage and then down-regulated at the postcondensation stage. Blockade of miRNA-488 via the use of PNA (peanut agglutinin)-based ASOs (antisense oligonucleotides) decreased the protein level of integrins β1 and phosphorylated FAK (focal adhesion kinase) and resulted in the suppression of cell motility and migration. Moreover, in parallel with theses observation, treatment of anti-miRNA-488 oligonucleotides up-regulated the level of MMP (matrix metalloprotease)-2 activity, and co-treatment with GM6001, an MMP inhibitor, induced recovery of cellular condensation inhibited by blockade of miRNA-488. Collectively, our results suggest that miRNA-488 is one of regulator in cell to ECM (extracellular matrix) interaction through modulation of focal adhesion activity by MMP-2 during chondrogenesis of limb mesenchymal cells.
    Cell Biology International 02/2011; 35(2):179-85. DOI:10.1042/CBI20100204 · 1.93 Impact Factor
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