PMID- 24095938
OWN - NLM
STAT- MEDLINE
DCOM- 20150219
LR  - 20220129
IS  - 1468-2060 (Electronic)
IS  - 0003-4967 (Linking)
VI  - 74
IP  - 1
DP  - 2015 Jan
TI  - Identification of small molecule inhibitors of RANKL and TNF signalling as 
      anti-inflammatory and antiresorptive agents in mice.
PG  - 220-6
LID - 10.1136/annrheumdis-2013-203700 [doi]
AB  - INTRODUCTION: Inflammatory joint diseases such as rheumatoid arthritis are 
      associated with local bone erosions and systemic bone loss, mediated by increased 
      osteoclastic activity. The receptor activator of nuclear factor (NF) kappaB ligand 
      (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas 
      tumour necrosis factor (TNF) plays a central role in the inflammatory process. 
      Here we tested whether a recently identified class of small molecule inhibitors 
      of RANKL signalling (ABD compounds) also affect TNF signalling and whether these 
      compounds inhibit inflammation in an animal model of rheumatoid arthritis. 
      METHODS: The inhibitory effects of the ABD compounds on TNF-induced signalling 
      were tested in mouse macrophage cultures by western blotting and in an NFkappaB 
      luciferase-reporter cell line. The anti-inflammatory effects of the compounds 
      were tested in the mouse collagen-induced arthritis model of rheumatoid 
      arthritis. RESULTS: The ABD compounds ABD328 and ABD345 both inhibited 
      TNF-induced activation of the NFkappaB pathway and the extracellular signal-regulated 
      kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When 
      tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the 
      compounds suppressed inflammatory arthritis, inhibited joint destruction and 
      prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed 
      oral activity. CONCLUSIONS: Here we describe a novel class of small molecule 
      compounds that inhibit both RANKL- and TNF-induced NFkappaB and MAPK signalling in 
      osteoclasts and macrophages, and inflammation and bone destruction in a mouse 
      model of rheumatoid arthritis. These novel compounds therefore represent a 
      promising new class of treatments for inflammatory diseases, such as rheumatoid 
      arthritis.
CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not 
      already granted under a licence) please go to 
      http://group.bmj.com/group/rights-licensing/permissions.
FAU - Coste, Emmanuel
AU  - Coste E
AD  - Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, 
      University of Edinburgh, General Western Hospital, Edinburgh, UK.
FAU - Greig, Iain R
AU  - Greig IR
AD  - School of Medical Sciences, Institute of Medical Sciences, University of 
      Aberdeen, Aberdeen, UK.
FAU - Mollat, Patrick
AU  - Mollat P
AD  - Galapagos SASU, Romainville, France.
FAU - Rose, Lorraine
AU  - Rose L
AD  - Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, 
      University of Edinburgh, General Western Hospital, Edinburgh, UK.
FAU - Gray, Mohini
AU  - Gray M
AD  - MRC Centre for Inflammation Research, The Queen's Medical Research Institute, 
      University of Edinburgh, Edinburgh, UK.
FAU - Ralston, Stuart H
AU  - Ralston SH
AD  - Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, 
      University of Edinburgh, General Western Hospital, Edinburgh, UK.
FAU - van 't Hof, Rob J
AU  - van 't Hof RJ
AD  - Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, 
      University of Edinburgh, General Western Hospital, Edinburgh, UK.
LA  - eng
GR  - 18328/ARC_/Arthritis Research UK/United Kingdom
GR  - 20035/ARC_/Arthritis Research UK/United Kingdom
GR  - G0901697/MRC_/Medical Research Council/United Kingdom
GR  - 17362/ARC_/Arthritis Research UK/United Kingdom
GR  - 20035/VAC_/Versus Arthritis/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131004
PL  - England
TA  - Ann Rheum Dis
JT  - Annals of the rheumatic diseases
JID - 0372355
RN  - 0 (ABD 328)
RN  - 0 (ABD345)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Hexanones)
RN  - 0 (NF-kappa B)
RN  - 0 (RANK Ligand)
RN  - 0 (Tumor Necrosis Factors)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/immunology/*metabolism
MH  - Arthritis, Rheumatoid/immunology/*metabolism
MH  - Biphenyl Compounds/*pharmacology
MH  - Bone Resorption/immunology/*metabolism
MH  - Hexanones/*pharmacology
MH  - MAP Kinase Signaling System/*drug effects/immunology
MH  - Mice
MH  - NF-kappa B/*drug effects/immunology/metabolism
MH  - RANK Ligand/*drug effects/immunology/metabolism
MH  - Signal Transduction/*drug effects
MH  - Tumor Necrosis Factors/immunology/*metabolism
OTO - NOTNLM
OT  - Osteoporosis
OT  - Rheumatoid Arthritis
OT  - TNF-alpha
EDAT- 2013/10/08 06:00
MHDA- 2015/02/20 06:00
CRDT- 2013/10/08 06:00
PHST- 2013/10/08 06:00 [entrez]
PHST- 2013/10/08 06:00 [pubmed]
PHST- 2015/02/20 06:00 [medline]
AID - annrheumdis-2013-203700 [pii]
AID - 10.1136/annrheumdis-2013-203700 [doi]
PST - ppublish
SO  - Ann Rheum Dis. 2015 Jan;74(1):220-6. doi: 10.1136/annrheumdis-2013-203700. Epub 
      2013 Oct 4.