LSJL downregulates EphrinB3. It upregulates Epha3 and Epha5
EphB/ephrin-B interactions mediate human MSC attachment, migration and osteochondral differentiation.
"EphB and ephrin-B molecules were expressed by ex vivo expanded human MSC populations and within human bone marrow trephine samples. To elucidate the contribution of EphB/ephrin-B molecules in MSC recruitment, we performed functional spreading and migration assays and showed that reverse ephrin-B signalling inhibited MSC attachment and spreading by activating Src-, PI3Kinase- and JNK-dependent signalling pathways. Forward EphB2 signalling promoted MSC migration by activating the Src kinase- and Abl-dependent signalling pathways. Activation of ephrin-B1 and/or ephrin-B2 molecules expressed by MSC was found to increase osteogenic differentiation, while ephrin-B1 activation promoted chondrogenic differentiation. These observations suggest that EphB/ephrin-B interactions may mediate the recruitment, migration and differentiation of MSC during bone repair."
"EphB2, EphB4 and ephrin-B1 expressions appeared most pronounced within the human bone, localising to bone lining cells, "
"ephrin-B3 was expressed by a large number of bone marrow cells"<-the downregulation of ephrinB3 in LSJL could be a sign of bone marrow cell differentiation.
"Blocking the EphB2 receptor, significantly inhibited GAG synthesis"
"the formation of a PDZ complex containing NHERF1, PTPN13 and TAZ with ephrin-B1 results in the dephosphorylation of TAZ, which allows its translocation into the nucleus and subsequent activation of osteogenic specific transcription factor, Osterix"
"In mice that lack the Hoxa13 gene, the mesenchymal condensations that form the autopod skeletal elements are poorly resolved, resulting in missing digit, carpal and tarsal elements. In addition, mesenchymal and endothelial cell layers of the umbilical arteries (UAs) are disorganized, resulting in their stenosis and in embryonic death. We generated a loss-of-function allele in which the GFP gene was targeted into the Hoxa13 locus. This allele allowed FACS isolation of mesenchymal cells from Hoxa13 heterozygous and mutant homozygous limb buds. Hoxa13(GFP) expressing mesenchymal cells from Hoxa13 mutant homozygous embryos are defective in forming chondrogenic condensations in vitro. Analysis of pro-adhesion molecules in the autopod of Hoxa13 mutants revealed a marked reduction in EphA7 expression in affected digits, as well as in micromass cell cultures prepared from mutant mesenchymal cells. Finally, antibody blocking of the EphA7 extracellular domain severely inhibits the capacity of Hoxa13(GFP) heterozygous cells to condense and form chondrogenic nodules in vitro, which is consistent with the hypothesis that reduction in EphA7 expression affects the capacity of Hoxa13(-/-) mesenchymal cells to form chondrogenic condensations in vivo and in vitro. EphA7 and EphA4 expression were also decreased in the mesenchymal and endothelial cells that form the umbilical arteries in Hoxa13 mutant homozygous embryos."
"the addition of the anti-EphA7 antibody dramatically reduced both cell adhesion and chondrogenic nodule formation of Hoxa13GFP heterozygous cells."
MicroRNA-34a regulates migration of chondroblast and IL-1β-induced degeneration of chondrocytes by targeting EphA5.
"We investigated the role of miRNA-34 during chondrogenic differentiation of chick limb mesenchymal cells. Expression of miR-34a increased upon chondrogenic inhibition. Blockade of miR-34a via PNA-based antisense oligonucleotides (ASOs) recovered the chondro-inhibitory actions of JNK inhibitor on migration of chondrogenic progenitors and the formation of precartilage condensation. EphA5 is a relevant target of miR-34a during chondrogenesis. MiR-34a was necessary and sufficient to down-regulate EphA5 expression, and up-modulation of EphA5 is sufficient to overcome inhibitory actions of miR-34 inhibition on cell migration and condensation of chick limb mesenchymal cells on collagen substrate. miR-34a is a negative modulator of chondrogenesis, particularly in migration of chondroblasts, by targeting EphA5 and resulting inhibition of cellular condensation during chondrogenesis of chick limb mesenchymal cells."
"In articular chondrocytes, Wnt-3a caused dedifferentiation of chondrocytes by upregulating the expression of c-Jun and its phosphorylation by JNK, resulting in activation of the c-Jun/activator protein. Treatment with transforming growth factor-β superfamily members promoted cartilage-specific gene expression during in vitro chondrogenic differentiation of mesenchymal progenitor cells from bone marrow and trabecular bone through activation of the mitogen-activated protein (MAP) kinases, p38, ERK-1, and JNK"
"miR-34a is one of key modulators in JNK-induced chondrogenic differentiation"
"EphA5 increases spreading and migration of chondroprogenitors in collagen substrate"
"the protein level of type II collagen decreased when cells were exposed to JNK inhibitors"
"miR-34a was significantly up-regulated by IL-1β and silencing of miR-34a significantly prevented IL-1β-induced down-regulation of type II collagen in rat chondrocytes. Increased expression level were observed in human articular chondrocytes exposed to IL-1β and human chondrocytes were prepared from osteoarthritic zone suggesting the involvement of miR-34a in the dedifferentiation of human articular chondrocytes by IL-1β. Co-treatment of miR-34a inhibitor induced the recovery of EphA5 level and type II collagen protein level which were suppressed by treatment of IL-1β. The expression level of EphA5 and type II collagen was significantly decreased in human chondrocytes were prepared from osteoarthritic zone"
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