IMD0354 通过抑制破骨细胞生成和骨吸收来发挥对骨稳态的新兴作用，而不影响骨形成。

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

机构信息

Department of Orthopaedics, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, Zhejiang, China.

Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

出版信息

Cell Death Dis. 2019 Sep 10;10(9):654. doi: 10.1038/s41419-019-1914-5.

DOI:10.1038/s41419-019-1914-5

PMID:31506437

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6737093/

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.

摘要

骨质疏松症是由骨形成和骨吸收之间的失衡引起的。核因子-κB 配体（RANKL）受体激活物通过激活核因子-κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路，促进破骨细胞的活性和分化。IMD 0354 是 NF-κB 激酶亚单位β（IKKβ）的选择性分子抑制剂，通过抑制 NF-κB 激活，对急性和亚急性炎症性疾病的治疗有效。然而，IMD 0354 对骨稳态的影响尚不清楚。在这项研究中，我们证明 IMD 0354 可显著减轻去卵巢诱导的骨丢失，并抑制小鼠破骨细胞生成，而骨形成不受影响。此外，IMD 0354 还可显著抑制 RANKL 和巨噬细胞集落刺激因子诱导的骨髓单核细胞中破骨细胞的分化和功能，通过抗酒石酸酸性磷酸酶（TRAP）染色和体外骨吸收测定得到验证。随后，我们发现 RANKL 诱导破骨细胞形成时 NF-κB 信号和 ERK/c-Fos 轴的激活被削弱。转录因子活化 T 细胞核因子 c1（NFATc1）和 c-Fos 的表达被抑制，破骨细胞相关基因的表达也随之下降。我们的研究结果表明，IMD 0354 可能是一种治疗骨质疏松症的潜在预防和治疗药物。