| Abstract |
Lipopolysaccharide (LPS) of Gram-negative bacteria in oral plaque is the major cause of periodontal disease. It is involved in the induction of inflammation and alveolar bone resorption at least partly by directly reacting to Toll-like receptor (TLR) 4 on osteoblasts. LPS induces osteoblasts to express proinflammatory cytokines, chemokines, and prostaglandins, as well as macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), which directly activate adjacent osteoclasts toward bone resorption. However, the regulator mechanisms have not been fully revealed at the molecular level. Here, we have demonstrated that LPS rapidly induces expression of early growth response 1 (EGR1), a zinc-finger transcription factor, and analyzed its physiological functions in osteoblasts. In both primary osteoblasts and an osteoblast cell line, LPS induced expression of EGR1 mRNA and protein within 30 min and 60 min, respectively, which were relatively slower than in macrophages. Inhibition of EGR1 by siRNA significantly inhibited LPS-induced mRNA expression of the tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokines, cyclooxygenase-2 (COX2), matrix metalloproteinase-13 (MMP13), M-CSF, and RANKL in osteoblasts. Moreover, forced overexpression of EGR1 by the inducible expression system was sufficient to increase mRNA expression levels of TNF, IL-6, COX2, MMP13, and RANKL without LPS stimulation. As for the intracellular signal transduction, LPS-induced EGR1 expression in osteoblasts was dependent on the unique c-Jun N-terminal kinase (JNK)-extracellular signal-regulated kinase (ERK) activation pathway. Our data suggest an essential role of EGR1 in osteoblast responses to LPS-inducing tissue inflammation and osteolysis, providing new insights into the pathogenesis of periodontal disease.
|
