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Necrostatin-7 Suppresses RANK-NFATc1 Signaling and Attenuates Macrophage to Osteoclast Differentiation

Necrostatin-7 Suppresses RANK-NFATc1 Signaling and Attenuates Macrophage to Osteoclast Differentiation

Hiroaki Fuji, Saori Ohmae, Naruto Noma, Masatoshi Takeiri, Hideto Yasutomi, Kazuya Izumi, Moe Ito, Masayasu Toyomoto, Soichiro Iwaki, Kenji Takemoto, Satoru Seo, Kojiro Taura, Shigeaki Hida, Mineyoshi Aoyama, etc.

Biochem Biophys Res Commun. 2018 Sep 5;503(2):544-549.

PMID: 29800570

Abstract:

Osteoclasts play a crucial role in osteolytic bone diseases, such as osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease of bone and bone metastatic tumors. Therefore, controlling osteoclast differentiation and function has been considered a promising therapeutic strategy. Here, we show that necrostatin (Nec)-7, an inhibitor of programmed necrosis, strongly suppressed receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption, without compromising macrophage colony-stimulating factor (M-CSF)-supported survival and growth of osteoclast precursor cells. Accordingly, Nec-7 significantly decreased the levels of RANKL-induced osteoclastogenic marker genes, such as cathepsin K. Mechanistically, Nec-7 neither affected MAPK nor NF-κB activation; however, it strongly inhibited the RANKL receptor (RANK) to nuclear factor of activated T cells c1 (NFATc1) signaling. Lentiviral expression of RANK in bone marrow-derived macrophages significantly restored osteoclastogenesis and NFATc1 amplification in Nec-7-treated cells. In this study, we revealed that Nec-7-sensitive pathways are crucially involved in osteoclast formation and function. Investigation of the molecular mechanism(s) through which Nec-7 inhibits RANK-NFATc1 signaling axis may lead to the development of new therapeutic strategies for bone disease.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP351062083	Necrostatin-7		351062-08-3	Price

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