Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice

Emmanuel Coste, Iain R Greig, Patrick Mollat, Lorraine Rose, Mohini Gray, Stuart H Ralston, Rob J van 't Hof

Research output: Contribution to journalArticle

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Abstract

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) κB 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 NFκB 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 NFκB 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 TNFinduced NFκB 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.
Original languageEnglish
Pages (from-to)220-226
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume74
Issue number1
Early online date4 Oct 2013
DOIs
Publication statusPublished - 1 Jan 2015

Fingerprint

Bone Density Conservation Agents
Rheumatoid Arthritis
Bone
Anti-Inflammatory Agents
Tumor Necrosis Factor-alpha
Molecules
Osteitis
Mitogen-Activated Protein Kinases
Experimental Arthritis
Bone and Bones
Collagen
Macrophages
MAP Kinase Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Luciferases
Joint Diseases
Osteoclasts
Cytoplasmic and Nuclear Receptors
Erosion
Animals

Keywords

  • RANKL
  • TNF signalling
  • small molecule inhibitors
  • anti inflammatory
  • antiresorptive agents

Cite this

Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice. / Coste, Emmanuel; Greig, Iain R; Mollat, Patrick; Rose, Lorraine; Gray, Mohini; Ralston, Stuart H; van 't Hof, Rob J.

In: Annals of the Rheumatic Diseases, Vol. 74, No. 1, 01.01.2015, p. 220-226.

Research output: Contribution to journalArticle

Coste, Emmanuel ; Greig, Iain R ; Mollat, Patrick ; Rose, Lorraine ; Gray, Mohini ; Ralston, Stuart H ; van 't Hof, Rob J. / Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice. In: Annals of the Rheumatic Diseases. 2015 ; Vol. 74, No. 1. pp. 220-226.
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N2 - 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) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in theinflammatory 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 mousemacrophage cultures by western blotting and in an NFκB 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 NFκB 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 TNFinduced NFκB 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.

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) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in theinflammatory 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 mousemacrophage cultures by western blotting and in an NFκB 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 NFκB 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 TNFinduced NFκB 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.

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