TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions

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Toll-like receptor(TLR)-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4(P3C) and Escherichia coli lipopolysaccharide(Ec LPS) were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism(Pg1690) or TLR4 antagonism(Pg1449) and mutant E. coli LPS(LPx E/LPx F/WSK) were used. IL-1b, SH2-containing inositol phosphatase-1(SHIP1) that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3a-Aminocholestane(3AC) was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3 C, poorly induced IL-1b but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, Ec LPS significantly induced IL-1b and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity.Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2(with SHIP1 activity) and mutant TLR4 ligands could enhance osteogenesis. Tumor-associated receptor (TLR) -mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 (P3C) Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism (Pg1690) or TLR4 antagonism (Pg1449) and mutant E. coli LPS (LPx E / LPx F / WSK (SH), which has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were. 3a-Aminocholestane (3AC) was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3 C, poorly induced IL-1b but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, Ec LPS significantly induced IL-1b and osteogenic mediators were not induced. While Pg Suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity.Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Furthermore, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 (with SHIP1 activity) and mutant TLR4 ligands could enhance osteogenesis.
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