The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption, but without affecting bone formation

Wenxiang Chen,Zhiwei Jie,Ziang Xie,Zhijun Hu,Xuesheng Jiang,Yongli Wang,Shunwu Fan,An Qin,Pan Tang

doi:10.1038/s41419-019-1914-5

Abstract

Osteoporosis is caused by an imbalance between bone formation and bone resorption. Receptor activator of nuclear factor-κB ligand (RANKL) promotes the activity and differentiation of osteoclasts via activating the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. IMD 0354 is a selective molecular inhibitor of inhibitor of NF-κB kinase subunit beta (IKKβ) and effective for treatment of acute and subacute inflammatory diseases through the suppression of NF-κB activation. However, the effect of IMD 0354 on bone homeostasis is unknown. In this study, we demonstrated that IMD 0354 significantly attenuated ovariectomy-induced bone loss and inhibited osteoclastogenesis in mice, whereas bone formation was not affected. Additionally, IMD 0354 dramatically inhibited osteoclast differentiation and function induced by RANKL and macrophage colony-stimulating factor in bone marrow monocytes as verified by tartrate-resistant acid phosphatase (TRAP) staining as well as bone resorption assay in vitro. Subsequently, we found that activation of NF-κB signaling and the ERK/c-Fos axis were blunted during osteoclast formation induced by RANKL. Transcription factors nuclear factor of activated T cells c1 (NFATc1) and c-Fos were suppressed with the decreased expression of osteoclast-related genes by IMD 0354. Our findings suggest that IMD 0354 could be a potential preventive and therapeutic drug for osteoporosis.

Highlights

Osteoporosis is known as the most common metabolic bone disease and is caused by an imbalance between bone formation and bone resorption[1], placing a substantial public health burden on the aging population[2,3]
Osteoclast differentiation derived from bone marrow monocytes/macrophages (BMMs) is mediated by receptor activator of nuclear factor-κB ligand (RANKL), a critical cytokine of the tumor necrosis factor (TNF) family, and its receptor RANK5,6
Through P62, TNF receptor-associated factor 6 (TRAF6) interacts with protein kinase C (PKC) or TGF-β-activated kinase 1-binding protein 2 (TAB2) and subsequently activates TGF-β-activated kinase 1 (TAK1), resulting in Official journal of the Cell Death Differentiation Association

Summary

Introduction

Osteoporosis is known as the most common metabolic bone disease and is caused by an imbalance between bone formation and bone resorption[1], placing a substantial public health burden on the aging population[2,3]. RANK–RANKL interaction promotes the differentiation of osteoclasts via directly activating several cellular signaling pathways, such as the nuclear factor-κB (NF-κB) cascade and mitogen-activated protein kinase (MAPK) signaling pathway[9]. Another crucial cytokine, macrophage colony-stimulating factor (M-CSF), is required for the differentiation of macrophage precursors to mature osteoclasts. The NF-κB, MAPK, and immune receptor tyrosine-based activation motif (ITAM) signaling pathways, converge to induce the expression of NFATc1, a key regulator that drives osteoclast differentiation, increasing the expression of osteoclast-related marker genes including dendritic cell-specific transmembrane protein (Dc-STAMP) and cathepsin K (CTSK)[10,11,12]

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