Home About us Contact
|
Home About us Contact | ||
|
|
||
Discoidin Domain Receptor (discoidin + domain_receptor)
Selected AbstractsDiscoidin domain receptor 1 mediates collagen-induced inflammatory activation of microglia in cultureJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2008Min-Chul Seo Abstract Discoidin domain receptor 1 (DDR1) is a nonintegrin collagen receptor tyrosine kinase with an extracellular domain homologous to discoidin 1 of a soil-living amoeba Dictyostelium discoideum. We have previously demonstrated that DDR1 mediates collagen-induced nitric oxide production in J774A.1 murine macrophages. Because collagen is one of the main components of extracellular matrix in the central nervous system, we hypothesized that collagen also induces inflammatory activation of brain microglia, and DDR1 may mediate collagen-induced microglial activation. Using BV-2 mouse microglial cells and mouse primary microglial cultures, we have demonstrated that (1) collagen induces inflammatory activation of microglia as evidenced by production of nitric oxide, expression of inducible nitric oxide synthase, COX-2, CD40, and matrix metalloproteinase,9; (2) DDR1 is expressed in microglia and is phosphorylated by collagen treatment; and (3) collagen-induced microglial activation is abrogated by DDR1 blockade but not by integrin neutralization. We have further shown that p38 MAPK, c-Jun N-terminal kinase, and nuclear factor,kappa B are involved in the collagen-DDR1-induced microglial activation. Our results suggest that collagen can induce inflammatory activation of brain microglia and that DDR1 mediates this effect of collagen in an integrin-independent manner. © 2007 Wiley-Liss, Inc. [source] Discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes,THE JOURNAL OF PATHOLOGY, Issue 2 2009Andreas R Klatt Abstract We deciphered constituent parts of a signal transduction cascade that is initiated by collagen II and results in the release of various pro-inflammatory cytokines, including interleukin-6 (IL-6), in primary human chondrocytes. This cascade represents a feed-forward mechanism whereby cartilage matrix degradation is exacerbated by the mutually inducing effect of released collagen II fragments and pro-inflammatory cytokines. We previously proposed discoidin domain receptor 2 as a central mediator in this event. Since this cascade plays a prominent role in the pathogenesis of osteoarthritis, our study further investigates the hypothesis that discoidin domain receptor 2 is a candidate receptor for collagen II, and that transcription factor NF,B, lipid kinase PI3K, and the MAP kinases are constituent parts of this very signal transduction cascade. To accomplish this, we selectively knocked down the molecules of interest in primary human chondrocytes, induced the specified cascade by incubating primary human chondrocytes with collagen II, and observed the outcome, specifically the changes in interleukin-6 release. Knockdown was performed by siRNA-mediated gene silencing in the case of discoidin domain receptor 2 (DDR2) or by using specific inhibitors for the remainder of the molecules. Results indicated that discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes and that MAP kinases p38, JNK and ERK, as well as transcription factor NF,B, are integral components of intracellular collagen II signalling. Given the detrimental role of these molecules in osteoarthritis, our findings provide new targets for more specific therapeutics, which may have fewer side effects than those currently applied. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 4 2008Huey-Huey Chua PhD Abstract Background. Nasopharyngeal carcinoma (NPC) is associated with Epstein-Barr virus (EBV) and has high metastatic potential. Discoidin domain receptors (DDR1, DDR2) are receptor-type tyrosine kinases activated by collagen. Their ability to induce expression of matrix metalloproteinase is related with tumor invasion. Therefore, we aim to investigate DDRs gene expression and its regulation in NPC. Methods and Results. By use of real-time quantitative polymerase chain reaction (Q-PCR), DDR2 gene expression but not DDR1 was significantly higher in primary and metastatic NPC. DDR2 was predominantly distributed in NPC tumor cells rather than in infiltrating lymphocytes. EBV Z-transactivator (Zta) transfection may distinctly elevate DDR2 level. Furthermore, data from reporter assay indicate that Zta could transactivate DDR2 promoter activity, suggesting the possible upregulation mechanism. Conclusion. DDR2 was differentially upregulated in NPC and modulated by EBV Zta protein. DDR2 may play a role in NPC invasion and serve as a diagnostic and therapeutic target. © 2007 Wiley Periodicals, Inc. Head Neck, 2008 [source] Regulation of chondrocyte differentiation by the actin cytoskeleton and adhesive interactionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2007Anita Woods Chondrocyte differentiation is a multi-step process characterized by successive changes in cell morphology and gene expression. In addition to tight regulation by numerous soluble factors, these processes are controlled by adhesive events. During the early phase of the chondrocyte life cycle, cell,cell adhesion through molecules such as N-cadherin and neural cell adhesion molecule (N-CAM) is required for differentiation of mesenchymal precursor cells to chondrocytes. At later stages, for example in growth plate chondrocytes, adhesion signaling from extracellular matrix (ECM) proteins through integrins and other ECM receptors such as the discoidin domain receptor (DDR) 2 (a collagen receptor) and Annexin V is necessary for normal chondrocyte proliferation and hypertrophy. Cell,matrix interactions are also important for chondrogenesis, for example through the activity of CD44, a receptor for Hyaluronan and collagens. The roles of several signaling molecules involved in adhesive signaling, such as integrin-linked kinase (ILK) and Rho GTPases, during chondrocyte differentiation are beginning to be understood, and the actin cytoskeleton has been identified as a common target of these adhesive pathways. Complete elucidation of the pathways connecting adhesion receptors to downstream effectors and the mechanisms integrating adhesion signaling with growth factor- and hormone-induced pathways is required for a better understanding of physiological and pathological skeletal development. J. Cell. Physiol. 213: 1,8, 2007. © 2007 Wiley-Liss, Inc. [source] Molecular Reproduction & Development: Volume 77, Issue 1MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 1 2010Article first published online: 17 NOV 200 Leydig cells in the seminiferous tubule co-express the lutenizing hormone receptor (LHR; red) and the discoidin domain receptor 2 (DDRs; green). Together, these receptors help maintain production of testosterone, which in turn regulates spermatogenesis. Kano et al. (page 29 in this issue) describe the effects of the loss of DDR2 on testicular function in mice. [source] Discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes,THE JOURNAL OF PATHOLOGY, Issue 2 2009Andreas R Klatt Abstract We deciphered constituent parts of a signal transduction cascade that is initiated by collagen II and results in the release of various pro-inflammatory cytokines, including interleukin-6 (IL-6), in primary human chondrocytes. This cascade represents a feed-forward mechanism whereby cartilage matrix degradation is exacerbated by the mutually inducing effect of released collagen II fragments and pro-inflammatory cytokines. We previously proposed discoidin domain receptor 2 as a central mediator in this event. Since this cascade plays a prominent role in the pathogenesis of osteoarthritis, our study further investigates the hypothesis that discoidin domain receptor 2 is a candidate receptor for collagen II, and that transcription factor NF,B, lipid kinase PI3K, and the MAP kinases are constituent parts of this very signal transduction cascade. To accomplish this, we selectively knocked down the molecules of interest in primary human chondrocytes, induced the specified cascade by incubating primary human chondrocytes with collagen II, and observed the outcome, specifically the changes in interleukin-6 release. Knockdown was performed by siRNA-mediated gene silencing in the case of discoidin domain receptor 2 (DDR2) or by using specific inhibitors for the remainder of the molecules. Results indicated that discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes and that MAP kinases p38, JNK and ERK, as well as transcription factor NF,B, are integral components of intracellular collagen II signalling. Given the detrimental role of these molecules in osteoarthritis, our findings provide new targets for more specific therapeutics, which may have fewer side effects than those currently applied. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in miceARTHRITIS & RHEUMATISM, Issue 9 2010Lin Xu Objective To investigate whether the reduction of discoidin domain receptor 2 (DDR-2), a cell membrane tyrosine kinase receptor for native type II collagen, attenuates the progression of articular cartilage degeneration in mouse models of osteoarthritis (OA). Methods Double-heterozygous (type XI collagen,deficient [Col11a1+/,] and Ddr2 -deficient [Ddr2+/,]) mutant mice were generated. Knee joints of Ddr2+/, mice were subjected to microsurgical destabilization of the medial meniscus. Conditions of the articular cartilage from the knee joints of the double-heterozygous mutant and surgically treated mice were examined by histology, evaluated using a modified Mankin scoring system, and characterized by immunohistochemistry. Results The rate of progressive degeneration in knee joints was dramatically reduced in the double-heterozygous mutant mice compared with that in the type XI collagen,deficient mice. The progression in the double-heterozygous mutant mice was delayed by ,6 months. Following surgical destabilization of the medial meniscus, the progressive degeneration toward OA was dramatically delayed in the Ddr2+/, mice compared with that in their wild-type littermates. The articular cartilage damage present in the knee joints of the mice was directly correlated with the expression profiles of DDR-2 and matrix metalloproteinase 13. Conclusion Reduction of DDR-2 expression attenuates the articular cartilage degeneration of knee joints induced either by type XI collagen deficiency or by surgical destabilization of the medial meniscus. [source] | |||||||||||||