Necrostatin-7 suppresses RANK-NFATc1 signaling and attenuates macrophage to osteoclast differentiation

作者：Fuji Hiroaki; Ohmae Saori; Noma Naruto; Takeiri Masatoshi; Yasutomi Hideto; Izumi Kazuya; Ito Moe; Toyomoto Masayasu; Iwaki Soichiro; Takemoto Kenji; Seo Satoru; Taura Kojiro; Hida Shigeaki; Aoyama Mineyoshi; Ishihama Yasushi; Hagiwara Masatoshi; Takeda Norihiko; Hatano Etsuro; Iwaisako Keiko; Uemoto Shinji; Asagiri Masataka^*

来源：Biochemical and Biophysical Research Communications, 2018, 503(2): 544-549.

DOI：10.1016/j.bbrc.2018.05.153

• Macrophage
• Osteoclast
• RANK
• RANKL
• NFATc1
• Necrostatin-7

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)-kappa B 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-kappa B activation; however, it strongly inhibited the RANKL receptor (RANK) to nuclear factor of activated T cells cl (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.

• 出版日期2018-9-5