A Nitrobenzoyl Sesquiterpenoid Insulicolide A Prevents Osteoclast Formation via Suppressing c-Fos-NFATc1 Signaling Pathway.

Yanhui Tan,Gang Huang,Xiaojuan Li,Minhong Ke,Yiyuan Wang,Yan Chen,Xuefeng Zhou,Jiehuang Zheng,Zhichao Li

doi:10.3389/fphar.2021.753240

Abstract

It is a viable strategy to inhibit osteoclast differentiation for the treatment of osteolytic diseases such as osteoporosis, rheumatoid arthritis and tumor bone metastases. Here we assessed the effects of insulicolide A, a natural nitrobenzoyl sesquiterpenoid derived from marine fungus, on receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and its protective effects on LPS-induced osteolysis mice model in vivo. The results demonstrated that insulicolide A inhibited osteoclastogenesis from 1 μM in vitro. Insulicolide A could prevent c-Fos and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) nuclear translocation and attenuate the expression levels of osteoclast-related genes and DC-STAMP during RANKL-stimulated osteoclastogenesis but have no effects on NF-κB and MAPKs. Insulicolide A can also protect the mice from LPS-induced osteolysis. Our research provides the first evidence that insulicolide A may inhibit osteoclastogenesis both in vitro and in vivo, and indicates that it may have potential for the treatment of osteoclast-related diseases.

Highlights

Bone resorption and formation are keeping a dynamic balance to maintain skeletal renewal and integrity
Bone erosion is caused by the increased number of bone-resorbing osteoclasts, so we evaluated the influence of insulicolide A on bone erosion of bone marrow monocytes (BMMs) on hydroxyapatite-coated plates
Our results indicated that marine-derived nitrobenzoyl sesquiterpenoid, insulicolide A, could attenuate osteoclastogenesis c-Fos-nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) signaling pathway induced by RANKL in vitro at doses from 1 to 2 μM

Summary

Introduction

Bone resorption and formation are keeping a dynamic balance to maintain skeletal renewal and integrity. Targeting osteoclast formation has been regarded as a practicable treatment strategy to improve the prognosis of patients with bone destructive diseases (Broadhead et al, 2011; Stickeler and Fehm, 2014). Osteoclasts, originate from bone marrow mononuclear macrophage lineage, are multinuclear and functioning as bone-resorbing cells (Boyle et al, 2003). Both receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are essential for proliferation. Activated NF-κB or c-Fos can induce the activation and amplification of the downstream nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), which can initiate the expression of osteoclast-related genes including OSCAR, Blimp, DCSTAMP, cathepsin K, TRAP, and so on (Takayanagi et al, 2002; Edwards and Mundy, 2011)

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