IL-1-induced receptor activator of NF-κB ligand in human periodontal ligament cells involves ERK-dependent PGE2 production

• Published in: Bone (New York, N.Y.) N.Y.), 2005-02, Vol.36 (2), p.267-275
• Main Authors: FUKUSHIMA, Hidefumi, JIMI, Eijiro, OKAMOTO, Fujio, MOTOKAWA, Wataru, OKABE, Koji
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - biosynthesis; Carrier Proteins - metabolism; Cells, Cultured; Coculture Techniques; Dinoprostone - biosynthesis; Dinoprostone - genetics; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - physiology; Facial bones, jaws, teeth, parodontium: diseases, semeiology; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Glycoproteins - metabolism; Humans; Interleukin-1 - pharmacology; Medical sciences; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - metabolism; Mice; NF-kappa B - biosynthesis; NF-kappa B - genetics; Non tumoral diseases; Osteoprotegerin; Otorhinolaryngology. Stomatology; Periodontal Ligament - cytology; Periodontal Ligament - drug effects; Periodontal Ligament - metabolism; Periodontium - cytology; Periodontium - drug effects; Periodontium - metabolism; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Tumor Necrosis Factor - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2004.09.011

Periodontitis, an inflammatory disorder of the supporting tissue of teeth, is one of the most common infectious diseases in humans. Periodontal pathogens promote inflammatory cytokines such as interleukin-1 (IL-1) and prostaglandin E2 (PGE2), resulting in alveolar bone destruction. In the present study, we examined the cellular and molecular mechanisms of IL-1-induced osteoclastogenesis using a coculture system of human periodontal ligament (PDL) cells and mouse spleen cells. IL-1alpha induced tartrate-resistant acid phosphatase positive (TRAP+) cell formation in a dose-dependent manner. IL-1alpha up-regulated receptor activator of NF-kappaB ligand (RANKL) and down-regulated osteoprotegerin (OPG) mRNA expression in PDL cells. The addition of cell-permeable PKI, an inhibitor of the cAMP/PKA signaling pathway, to the cocultures 8 h after the IL-1alpha stimulation inhibited IL-1alpha-induced TRAP+ cell formation. IL-1alpha-induced TRAP+ cell formation was completely blocked by either NS398, a selective inhibitor of cyclooxygenase (COX)-2, or PD98059, a specific inhibitor of extracellular signal-regulated kinase (ERK). Pretreatment with NS398 and PD98059 also inhibited both the up-regulation of RANKL and the down-regulation of OPG expression by IL-1alpha in PDL cells. IL-1alpha activated ERK phosphorylation and PD98059 greatly inhibited both COX-2 mRNA expression and PGE(2) production induced by IL-1alpha in PDL cells. In contrast, NEMO binding domain (NBD) peptide, a specific inhibitor of NF-kappaB signaling, did not affect COX2, RANKL, or OPG mRNA expression induced by IL-1alpha. These results suggest that IL-1alpha stimulates osteoclast formation by increasing the expression level of RANKL versus OPG via ERK-dependent PGE2 production in PDL cells.