Central role of SREBP-2 in the pathogenesis of osteoarthritis
| Autor: | F. Kostopoulou, Dimitrios Iliopoulos, Vasiliki Gkretsi, Pagona Oikonomou, Aspasia Tsezou, Konstantinos N. Malizos, Lazaros Poultsides |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Gene Expression lcsh:Medicine Pathogenesis Phosphatidylinositol 3-Kinases chemistry.chemical_compound Transforming Growth Factor beta Molecular Cell Biology Aggrecans Phosphorylation lcsh:Science Cells Cultured Aged 80 and over Regulation of gene expression Genetics Multidisciplinary Middle Aged Cell biology Phenotype Medicine Female lipids (amino acids peptides and proteins) Oligopeptides Protein Binding Sterol Regulatory Element Binding Protein 2 Research Article Adult Heterozygote Genotype Proto-Oncogene Proteins c-akt Biology Peptides Cyclic Polymorphism Single Nucleotide Collagen Type I Molecular Genetics Chondrocytes Rheumatology Osteoarthritis Humans Genetic Predisposition to Disease Smad3 Protein Collagen Type II Transcription factor Alleles Aged Evolutionary Biology Population Biology Cholesterol lcsh:R Computational Biology Human Genetics Lipid metabolism Integrin alphaV Hydroxycholesterols Sterol regulatory element-binding protein Gene Expression Regulation chemistry Genetics of Disease Hydroxymethylglutaryl CoA Reductases lcsh:Q Sterol regulatory element-binding protein 2 Receptors Transforming Growth Factor beta Population Genetics |
| Zdroj: | PLoS ONE, Vol 7, Iss 5, p e35753 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Recent studies have implied that osteoarthritis (OA) is a metabolic disease linked to deregulation of genes involved in lipid metabolism and cholesterol efflux. Sterol Regulatory Element Binding Proteins (SREBPs) are transcription factors regulating lipid metabolism with so far no association with OA. Our aim was to test the hypothesis that SREBP-2, a gene that plays a key role in cholesterol homeostasis, is crucially involved in OA pathogenesis and to identify possible mechanisms of action. Methodology/Principal Findings We performed a genetic association analysis using a cohort of 1,410 Greek OA patients and healthy controls and found significant association between single nucleotide polymorphism (SNP) 1784G>C in SREBP-2 gene and OA development. Moreover, the above SNP was functionally active, as normal chondrocytes’ transfection with SREBP-2-G/C plasmid resulted in interleukin-1β and metalloproteinase-13 (MMP-13) upregulation. We also evaluated SREBP-2, its target gene 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR), phospho-phosphoinositide3-kinase (PI3K), phospho-Akt, integrin-alphaV (ITGAV) and transforming growth factor-β (TGF-β) mRNA and protein expression levels in osteoarthritic and normal chondrocytes and found that they were all significantly elevated in OA chondrocytes. To test whether TGF-β alone can induce SREBP-2, we treated normal chondrocytes with TGF-β and found significant upregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13. We also showed that TGF-β activated aggrecan (ACAN) in chondrocytes only through Smad3, which interacts with SREBP-2. Finally, we examined the effect of an integrin inhibitor, cyclo-RGDFV peptide, on osteoarthritic chondrocytes, and found that it resulted in significant upregulation of ACAN and downregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13 expression levels. Conclusions/Significance We demonstrated, for the first time, the association of SREBP-2 with OA pathogenesis and provided evidence on the molecular mechanism involved. We suggest that TGF-β induces SREBP-2 pathway activation through ITGAV and PI3K playing a key role in OA and that integrin blockage may be a potential molecular target for OA treatment. |
| Databáze: | OpenAIRE |
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