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
  • 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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