Dauricine Protects from LPS-Induced Bone Loss via the ROS/PP2A/NF-κB Axis in Osteoclasts.

Hyun-Jung Park,Jae-Hee Suh,Malihatosadat Gholam Zadeh,Hye-Seon Choi

doi:10.3390/antiox9070588

Hyun-Jung Park, Jae-Hee Suh + Show 2 more

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https://doi.org/10.3390/antiox9070588

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Abstract

Dauricine (DAC), an isoquinoline alkaloid, exhibits anti-inflammatory activity. We hypothesized that DAC may prevent the inflammatory bone loss induced by lipopolysaccharide (LPS). LPS-induced bone loss was decreased by DAC in female C57BL/6J mice as evaluated by micro-computerized tomography (μCT) analysis. In vivo tartrate-resistant acid phosphatase (TRAP) staining showed that the increased number of osteoclasts (OCs) in LPS-treated mice was attenuated by DAC, indicating that DAC exhibited bone sparing effects through acting on OCs. DAC also decreased the differentiation and activity of OCs after LPS stimulation in vitro. LPS-induced cytosolic reactive oxygen species (cROS) oxidized PP2A, a serine/threonine phosphatase, leading to the activation of IKKα/β, followed by the nuclear localization of p65. DAC decreased LPS-induced ROS, resulting in the recovery of the activity of PP2A by reducing its oxidized form. Consequently, DAC reduced the phosphorylation of IKKα/β to block the nuclear localization of p65, which decreased NF-κB activation. Taken together, DAC reduced the differentiation and activity of OCs by decreasing ROS via the ROS/PP2A/NF-κB axis, resulting in protection from LPS-induced bone loss. We have demonstrated that LPS-induced bone loss was inhibited by DAC via its action on OCs, implying the therapeutic potential of DAC against inflammatory bone loss.

Highlights

Inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and Crohn’s disease have been reported to be associated with severe bone loss [1,2,3]
Receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor-α (TNF-α), and IL-17 contribute to bone loss via influencing bone cells [7]
Femurs from mice treated with DAC or vehicle after the injection of LPS or PBS were analyzed using μCT in order to investigate the effect of DAC on LPS-induced inflammatory bone loss

Summary

Introduction

Inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and Crohn’s disease have been reported to be associated with severe bone loss [1,2,3]. Inflammation-induced bone loss affects the stability of the skeleton, leading to an increased fracture risk [4]. Mesenchymal cells, and the neighboring microenvironment all affect inflammatory bone destruction, osteoclasts (OCs) are key players in osteolysis [5]. Immune cells and their related products affect bone density through their effects on bone cells. The secreted products of immune cells infiltrating due to inflammation maintain the inflammatory response, which initially recruits OC and enhances OC formation and OC activity. Lipopolysaccharide (LPS) treatment induces systemic inflammation along with severe bone loss via the activity of OCs [8,9,10]. LPS has been reported to enhance the differentiation, survival, and function of OCs [11,12,13,14]

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