2. Academic Validation
  3. Necrostatin-7 suppresses RANK-NFATc1 signaling and attenuates macrophage to osteoclast differentiation

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

  • Biochem Biophys Res Commun. 2018 Sep 5;503(2):544-549. doi: 10.1016/j.bbrc.2018.05.153.
Hiroaki Fuji 1,  Saori Ohmae 2,  Naruto Noma 3,  Masatoshi Takeiri 3,  Hideto Yasutomi 4,  Kazuya Izumi 4,  Moe Ito 4,  Masayasu Toyomoto 5,  Soichiro Iwaki 4,  Kenji Takemoto 6,  Satoru Seo 1,  Kojiro Taura 1,  Shigeaki Hida 7,  Mineyoshi Aoyama 4,  Yasushi Ishihama 8,  Masatoshi Hagiwara 5,  Norihiko Takeda 9,  Etsuro Hatano 10,  Keiko Iwaisako 11,  Shinji Uemoto 1,  Masataka Asagiri 12
Affiliations

Affiliations

  • 1 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 2 Department of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
  • 3 Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 4 Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
  • 5 Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 6 Center for Cell Death, Injury and Regeneration, Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
  • 7 Department of Molecular and Cellular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
  • 8 Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
  • 9 Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 10 Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
  • 11 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan. Electronic address: [email protected].
  • 12 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan. Electronic address: [email protected].
PMID: 29800570 DOI: 10.1016/j.bbrc.2018.05.153
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.

Keywords

Macrophage; NFATc1; Necrostatin-7; Osteoclast; RANK; RANKL.

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