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Via the protein kinase a and extracellular signal-regulated.
| Content Provider | CiteSeerX |
|---|---|
| Author | Tseng, Wendy |
| Abstract | Epidemiological evidence suggests a relationship between cardiovascular disease and osteoporosis, a disease where bones become fragile due to imbalance between bone resorption and formation. We previously found that differentiation of bone-forming osteoblasts is inhibited by oxidized lipoproteins, which trigger the pathogenesis of atherosclerosis. Since differentiation of bone-resorbing osteoclasts depends on cytokines produced by osteoblasts, we hypothesize that oxidized phospholipids may also regulate bone resorption by altering osteoblastic expression of such cytokines, including interleukin-6 (IL-6). This study investigated the regulatory mechanism of IL-6 expression by oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (ox-PAPC), an active component of oxidized lipoproteins. In murine calvarial preosteoblasts, ox-PAPC increased IL-6 mRNA expression and activated IL-6 promoter luciferase reporter constructs. Protein kinase A (PKA) inhibitor H89 reduced ox-PAPC induction of IL-6, whereas mutations in the binding sites for nuclear factor κB (NF-κB) or CCAAT/enhancer binding protein (C/EBP) transcription factors did not attenuate ox-PAPC-induced IL-6 promoter activity. These results suggest that PKA, but not NF-κB or C/EBP, mediates the ox-PAPC effect. Western blot analysis showed that ox-PAPC also activated extracellular signal-regulated kinase (ERK). However, ERK inhibition further increased ox-PAPC induction of IL-6, while ERK activation decreased PKA activation of IL-6, suggesting that the ERK pathway antagonizes the PKA pathway to inhibit IL-6 expression. Together, the data suggest oxidized phospholipids increase IL-6 expression in osteoblasts by activating the PKA and ERK pathways, implicating the osteoclast-regulating cytokine IL-6 as a possible link between cardiovascular disease and osteoporosis. |
| File Format | |
| Access Restriction | Open |
| Subject Keyword | Extracellular Signal-regulated Protein Kinase Il-6 Expression Oxidized Lipoprotein Oxidized Phospholipid Erk Pathway Cardiovascular Disease Bone Resorption Ox-papc Induction Murine Calvarial Preosteoblasts Erk Inhibition Bone-forming Osteoblast Osteoclast-regulating Cytokine Il-6 Erk Activation Whereas Mutation Active Component Regulatory Mechanism Extracellular Signal-regulated Kinase Western Blot Analysis Ox-papc Effect Il-6 Mrna Expression Transcription Factor Inhibitor H89 Il-6 Promoter Luciferase Reporter Construct Epidemiological Evidence Osteoblastic Expression Bone-resorbing Osteoclast Pka Pathway Nuclear Factor Binding Site Possible Link Ox-papc-induced Il-6 Promoter Activity Pka Activation |
| Content Type | Text |
