Linked Life Data

21148317

Source:http://linkedlifedata.com/resource/pubmed/id/21148317

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2011-2-14
pubmed:abstractText
Elevated homocysteine (Hcys) serum levels represent a risk factor for several chronic pathologies, including cardiovascular disease, atherosclerosis, and chronic renal failure, and affect bone development, quality, and homeostasis. Hcys influences the formation of a stable bone matrix directly through the inhibition of the collagen cross-linking enzyme lysyl oxidase (Lox) and, as we have shown recently, by repressing its mRNA expression. The aim of this study was to investigate the mechanisms involved in this process. Through evaluation of gene arrays, quantitative RT-PCR, immunoblots, and ELISA, we identified a Hcys-dependent stimulation of interleukin 6 (IL-6) and genes involved in IL-6/Janus kinase 2 (JAK2)-dependent signal transduction pathways in pre-osteoblastic MC3T3-E1 cells. Moreover, up-regulation of genes essential for epigenetic DNA methylation (DNA (cytosine-5)-methyltransferases and helicase lymphoid-specific (Hells) was observed. Further investigations demonstrated that Hcys increased via IL-6/JAK2 the expression of Fli1 (Friend leukemia virus integration 1), a transcription factor, which we found essential for IL-6-dependent Dnmt1 stimulation. CpG methylation analysis of CpG-rich Lox proximal promoter revealed an increased CpG methylation status after treatment of the cells with Hcys indicating an epigenetic origin for Hcys-dependent Lox repression. Inhibition of the IL-6/JAK2 pathway or of CpG methylation reversed the repressive effect of Hcys on Lox expression. In conclusion, we demonstrate that Hcys stimulates IL-6 synthesis in osteoblasts, which is known to affect bone metabolism via osteoclasts. Furthermore, IL-6 stimulation results via JAK2, Fli1, and Dnmt1 in down-regulation of Lox expression by epigenetic CpG methylation revealing a new mechanism negatively affecting bone matrix formation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/DNA (Cytosine-5-)-Methyltransferase, http://linkedlifedata.com/resource/pubmed/chemical/DNA..., http://linkedlifedata.com/resource/pubmed/chemical/DNA Helicases, http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Matrix Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Fli1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Hells protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Homocysteine, http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-6, http://linkedlifedata.com/resource/pubmed/chemical/Jak2 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Janus Kinase 2, http://linkedlifedata.com/resource/pubmed/chemical/Lox protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Protein-Lysine 6-Oxidase, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Protein c-fli-1
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
18
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5578-88
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Homocysteine suppresses the expression of the collagen cross-linker lysyl oxidase involving IL-6, Fli1, and epigenetic DNA methylation.
pubmed:affiliation
1st Medical Department, Hanusch Hospital, Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Wiener Gebietskrankenkasse and AUVA Trauma Center Meidling, 1140 Vienna, Austria.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't