Abstract
BackgroundLectin-like oxidized low-density-lipoprotein receptor 1 (Lox-1) is the receptor for oxidized low-density lipoprotein (oxLDL), a mediator in dyslipidemia. Toll-like receptor (TLR)-2 and − 4 are receptors of lipopolysaccharide (LPS) from Porphyromonas gingivalis, a major pathogen of chronic periodontitis. Although some reports have demonstrated that periodontitis has an adverse effect on dyslipidemia, little is clear that the mechanism is explained the effects of dyslipidemia on osteoclastogenesis. We have hypothesized that osteoclast oxLDL has directly effect on osteoclasts (OCs), and therefore alveolar bone loss on periodontitis may be increased by dyslipidemia. The present study aimed to elucidate the effect of Lox-1 on osteoclastogenesis associated with TLRs in vitro.MethodsMouse bone marrow cells (BMCs) were stimulated with macrophage colony-stimulating factor into bone marrow macrophages (BMMs). The cells were also stimulated with synthetic ligands for TLR2 (Pam3CSK4) or TLR4 (Lipid A), with or without receptor activator of nuclear factor kappa-B ligand (RANKL), and assessed for osteoclastogenesis by tartrate-resistant acid phosphatase (TRAP) staining, immunostaining, western blotting, flow activated cell sorting (FACS) analysis, real-time polymerase chain reaction (PCR), and reverse transcription PCR.ResultsLox-1 expression was significantly upregulated by Pam3CSK4 and Lipid A in BMCs (p < 0.05), but not in BMMs. FACS analysis identified that Pam3CSK4 upregulated RANK and Lox-1 expression in BMCs. TRAP-positive cells were not increased by stimulation with Pam3CSK4 alone, but were increased by stimulation with combination combined Pam3CSK and oxLDL. Expression of both Lox-1 and myeloid differentiation factor 88 (MyD88), an essential adaptor protein in the TLR signaling pathway, were suppressed by inhibitors of TLR2, TLR4 and mitogen-activated protein kinase (MAPK).ConclusionsThis study supports that osteoclastogenesis is promoted under the coexistence of oxLDL by TLR2-induced upregulation of Lox-1 in BMCs. This indicates that periodontitis could worsen with progression of dyslipidemia.
Highlights
Lectin-like oxidized low-density-lipoprotein receptor 1 (Lox-1) is the receptor for oxidized low-density lipoprotein, a mediator in dyslipidemia
We showed that osteoclastogenesis was accelerated by activation of Toll-like receptor (TLR) through upregulation of lipoprotein receptor-1 (Lox-1) expression during bone marrow cell (BMC) differentiation into Bone marrow macrophage (BMM), suggesting dyslipidemia increases the risk of periodontitis
Expression of Lox-1 was upregulated by TLR 2/4 ligands in BMCs To clarify the effect of TLR ligands on the expression of Lox-1 in BMCs or BMMs, cells were cultured with or without Pam3CSK4 (100 ng/ml) or Lipid A (100 ng/ml) in the presence of macrophage colony-stimulating factor (M-CSF) for 3 days (Fig. 1a)
Summary
Lectin-like oxidized low-density-lipoprotein receptor 1 (Lox-1) is the receptor for oxidized low-density lipoprotein (oxLDL), a mediator in dyslipidemia. Toll-like receptor (TLR)-2 and − 4 are receptors of lipopolysaccharide (LPS) from Porphyromonas gingivalis, a major pathogen of chronic periodontitis. We have hypothesized that osteoclast oxLDL has directly effect on osteoclasts (OCs), and alveolar bone loss on periodontitis may be increased by dyslipidemia. OCs require macrophage colony-stimulating factor (M-CSF) for proliferation and receptor activator of nuclear factor kappa-B ligand (RANKL) for fusion and maturation [1,2,3,4,5]. It has been reported that P. gingivalis LPS stimulates periosteal OC formation due to induction of RANKL in osteoblasts by activation of TLR2 [15]. Synthetic TLR2 ligand inhibits OC formation in mouse bone marrow macrophages (BMMs) stimulated with macrophage colony-stimulating factor (M-CSF) and RANKL [18, 19]. P. gingivalis has known to promote osteoclastogenesis and bone resorption which types of TLR receptor, such as TLR2 and/or TLR4 promote bone resorption remains unclear
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