Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation.
Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study, we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that 'read' chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis macrophages and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption.
1] Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA [2] Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
Kyung-Hyun
KH
Park-Min
Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA.
Elisha
E
Lim
Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA.
Min Joon
MJ
Lee
Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA.
Sung Ho
SH
Park
1] Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA [2] Biological Sciences Department, New York City College of Technology, City University of New York, New York, New York 10021, USA.
Eugenia
E
Giannopoulou
Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA.
Anna
A
Yarilina
1] Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca 14850, USA [2] Musculoskeletal Integrity Program, Hospital for Special Surgery, New York, New York 11201, USA.
Marjolein
M
van der Meulen
1] Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA [2] Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
Baohong
B
Zhao
Epinova DPU, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
Nicholas
N
Smithers
Epinova DPU, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
Jason
J
Witherington
Epinova DPU, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
Kevin
K
Lee
Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
Paul P
PP
Tak
Epinova DPU, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
Rab K
RK
Prinjha
1] Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York 10021, USA [2] Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA [3] Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York 10021, USA.
Lionel B
LB
Ivashkiv
D000818:Animals; D001862:Bone Resorption / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D010024:Osteoporosis / Q000503:physiopathology; D010052:Ovariectomy; D053245:RANK Ligand / Q000502:physiology
C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D053245:RANK Ligand