Extracellular Prdx1 mediates bacterial infection and inflammatory bone diseases.

AIM: We aimed to determine the role of extracellular peroxiredoxin 1 (Prdx1) in the pathogenesis of bacterial infections and inflammatory bone disease. MATERIALS AND METHODS: We first investigated the role of Prdx1 using knockout mice. Next, we determined the role of extracellular Prdx1 in bacterial infections by using a neutralizing antibody against Prdx1. We finally investigated whether blockade of extracellular Prdx1 affected high- or low-grade inflammatory bone diseases using calvarial osteolysis, collagen-induced arthritis (CIA), and microgravity-induced bone loss in mouse models. KEY FINDINGS: The lack of Prdx1 increased susceptibility to infections by Listeria monocytogenes or Escherichia coli. Prdx1 is released into the serum upon E. coli infection, and blockade of extracellular Prdx1 confers significant protection against bacterial infections. Our data suggested that circulating Prdx1 is increased by the development of osteolytic disease, and that blockade of extracellular Prdx1 exerts therapeutic effects against high- and low-grade inflammatory bone loss. In addition, the release of Prdx1 under inflammatory osteolytic conditions partly depends on non-canonical TIR-domain-containing adapter-inducing interferon-ß (TRIF)-caspase-11-gasdemin D (GSDMD) inflammasome pathways. SIGNIFICANCE: Extracellular Prdx1 is involved in the development of bacterial infections and inflammatory bone disease. Thus, extracellular Prdx1 may represent a novel therapeutic target for bacterial infections or inflammatory osteolytic diseases.

Iris Koreana NAKAI Inhibits Osteoclast Formation via p38-Mediated Nuclear Factor of Activated T Cells 1 Signaling Pathway.

BACKGROUND: Iris Koreana NAKAI (IKN) is a flowering perennial plant that belongs to the Iridaceae family. In this study, we aimed to demonstrate the effects of IKN on osteoclast differentiation in vitro and in vivo. We also sought to verify the molecular mechanisms underlying its anti-osteoclastogenic effects. METHODS: Osteoclasts were formed by culturing mouse bone marrow macrophage (BMM) cells with macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL). Bone resorption assays were performed on dentin slices. mRNA expression levels were analyzed by quantitative polymerase chain reaction. Western blotting was performed to detect protein expression or activation. Lipopolysaccharide (LPS)-induced osteoclast formation was performed using a mouse calvarial model. RESULTS: In BMM cultures, an ethanol extract of the root part of IKN suppressed RANKL-induced osteoclast formation and bone resorptive activity. In contrast, an ethanol extract of the aerial parts of IKN had a minor effect on RANKL-induced osteoclast formation. Mechanistically, the root part of IKN suppressed RANKL-induced p38 mitogen-activated protein kinase (MAPK) activation, effectively abrogating the induction of c-Fos and nuclear factor of activated T cells 1 (NFATc1) expression. IKN administration decreased LPS-induced osteoclast formation in a calvarial osteolysis model in vivo. CONCLUSIONS: Our study suggested that the ethanol extract of the root part of IKN suppressed osteoclast differentiation and function partly by downregulating the p38 MAPK/c-Fos/NFATc1 signaling pathways. Thus, the root part.

Anti­osteoclastogenic effects of Coriandrum sativum L. via the NF­κB and ERK­mediated NFATc1 signaling pathways.

Coriandrum sativum L. (CSL) is an aromatic plant that belongs to the Apiaceae family. The present study aimed to determine the effects of the ethanol extract of the aerial part of CSL on osteoclast formation in vitro and in vivo, and the underlying molecular mechanism of its anti­osteoclastogenic effect. The levels of osteoclast formation and bone resorption were evaluated by tartrate­resistant acid phosphatase staining and bone resorption pit assays. The expression levels of osteoclast­related molecules were analyzed by reverse transcription­quantitative PCR and western blotting. The ethanol extract of CSL suppressed osteoclast formation in a mouse co­culture system. In osteoblasts, CSL exerted a minor effect on the mRNA ratio of receptor activator of nuclear factor­κB (NF­κB) ligand (RANKL) to osteoprotegerin, suggesting a direct effect of CSL on osteoclast precursors. Notably, CSL inhibited RANKL­induced osteoclast differentiation and bone resorption activity in bone marrow­derived macrophage cultures. Mechanistically, CSL abolished RANKL­induced NF­κB and extracellular signal­regulated kinase (ERK) MAPK activation, which effectively impaired the induction of c­Fos and nuclear factor of activated T cells (NFATc1). Finally, the ethanol extract of CSL prevented osteoclast formation in a lipopolysaccharide­induced calvarial bone loss model in vivo. The findings of the present study suggested that CSL may suppress osteoclast differentiation and function by downregulating the NF­κB and ERK/c­Fos/NFATc1 signaling pathways. Thus, CSL could be explored as a potential candidate for the prevention and treatment of osteolytic diseases.