Inhibitory effects of orally administrated liposomal bovine lactoferrin on the LPS-induced osteoclastogenesis

Abstract

Bovine lactoferrin (bLF) modulates the production of proinflammatory cytokines including tumor necrosis factor (TNF)-a, and may thus control alveolar bone destruction associated with periodontitis. In this study, the effects of bLF on mRNA expression in lipopolysaccharide (LPS)-stimulated osteoblasts (OBs) and on LPS-induced osteoclastogenesis were examined. The inhibitory effects of oral administration of liposomal-bLF (L-bLF), which improved the robustness of bLF to digestive enzymes, on alveolar bone resorption using LPS-induced periodontitis rat model are also reported. Three groups of 7-week-old male Wistar rats were treated with L-bLF (L-bLF group), bLF (bLF group), or the vehicle (control group) in drinking water (n ¼ 6 in each group). On day 7, LPS was topically applied into the gingival sulcus. Number of osteoclasts and immunoexpression of TNF-a were analyzed. The bLF inhibited the upregulation of TNF-a-mRNA-and upregulation of receptor activator of NFkB (RANKL)-mRNA expression and eliminated downregulation of osteoprotegerin (OPG)-mRNA expression in LPS-stimulated OBs and reduced LPS-induced osteoclastogenesis in co-culture with primary OBs and bone marrow cells. In the control group, the number of osteoclasts increased after LPS treatment. The number of osteoclasts that appeared along the alveolar bone margin was significantly reduced (Po0.01) in the L-bLF but not in the bLF group. Furthermore, L-bLF suppressed upregulation of TNF-a immunoexpression in periodontal tissue and TNF-a and interleukin (IL)-1b-mRNA level in gingival tissue. The results of this study indicate that oral administration of L-bLF significantly reduces alveolar bone resorption induced by LPS stimulation through inhibition of TNF-a production and modulation of RANKL/OPG balance in OBs. It is suggested that L-bLF could be a potent therapeutic and preventive agent for attenuating alveolar bone destruction in periodontitis patients.

Bone Regeneration Is Promoted by Orally Administered Bovine Lactoferrin in a Rabbit Tibial Distraction Osteogenesis Model

“…The results of RT-PCR and immunohistochemical analysis indicated that bovine lactoferrin treatment not only increased the expression level of OPG but also slightly decreased the expression level of RANKL in the distraction gap, leading to a significantly lower RANKL/OPG ratio in the distracted calluses compared with the untreated distraction osteogenesis group. Our results agree with those of previous studies [11,35] indicating that the OPG/RANKL/RANK system might be a major mechanism for increased bone formation and decreased bone resorption in distraction osteogenesis using bovine lactoferrin treatment.…”

Molecular Mechanisms of the Inhibitory Effects of Bovine Lactoferrin on Lipopolysaccharide-mediated Osteoclastogenesis

“…In our previous study we demonstrated that oral administration of liposomal bLF, which exhibits improved stability in the stomach and enhanced absorption by the intestinal tract, significantly reduces alveolar bone resorption by decreasing TNF-␣ production by host cells stimulated with LPS (3). In addition, our in vitro analysis showed that bLF pretreatment inhibits LPS-induced TNF-␣ and RANKL (receptor activator of nuclear factor B ligand) expression in ST2 cells (a bone marrow-derived osteogenic cell line).…”

Human Trial of Liposomal Lactoferrin Supplementation for Periodontal Disease

“…We have already demonstrated that many positive cells to a bLF antibody were immunohistochemically detected in periodontal tissue of LbLF-fed rats, 20) which suggests that bLF or its fragment absorbed from the intestine might show anti-inflammatory effects in this study, although further study is needed to elucidate the biological mechanism of L-bLF. On the other hand, we have already reported that soy phosphatidylcholine itself inhibited TLR4-mediated MCP-1 expression in vascular cells.…”

“…Our previous studies have shown that the oral administration of liposomal bLF (L-bLF) exhibited more suppressive effects than non-liposomal bLF on LPS-induced TNF-a production from mouse PBMCs, 19) as well as on osteoclast increase or TNF-a expression in marginal periodontal tissue of a rat LPS-induced periodontitis model. 20) In the present study, LbLF was orally administered to subjects with periodontal disease to investigate whether it can be useful for treating periodontal disease. …”