Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

OBJECTIVES: To evaluate the clinical efficacy of a novel synthetic peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, CLX-090717, in several in vitro cell culture systems and murine CIA, an experimental model of RA. METHODS: Peripheral blood monocytes purified by elutriation, and rheumatoid synovial cells isolated from clinical tissue were cultured with CLX-090717 and TNF-alpha release was measured. Molecular mechanism of action was analysed by western blotting and electrophoretic mobility shift assay. Thioglycollate-elicited murine peritoneal macrophages were cultured with CLX-090717 and lipopolysaccharide (LPS)-induced TNF-alpha release was assayed. Therapeutic studies were done in mice with established arthritis by evaluating clinical parameters and histology. In addition, type II collagen response of lymphocytes from mice with CIA was examined. RESULTS: CLX-090717 significantly inhibited spontaneous TNF-alpha release by RA synovial membrane cells, as well as LPS-induced TNF-alpha release from human and murine monocytic cells. Inhibition of TNF-alpha in monocytes was mediated partially through a nuclear factor-kappaB (NF-kappaB)-dependent pathway, as judged by sustained levels of IkappaBalpha in cytosolic extracts and a reduced level of LPS-induced NF-kappaB activity in nuclear extracts. CLX-090717 reduced clinical signs of arthritis and damage to joint architecture when administered therapeutically to arthritic mice. Mechanisms of action in CIA involved the reduction in proliferation of arthritic lymphocytes to antigen in vitro as well as reduced TNF-alpha release. CONCLUSIONS: Our data suggest that the synthetic compound CLX-090717 has potential as a small molecular weight anti-inflammatory therapeutic for chronic inflammatory conditions.

Original publication

DOI

10.1093/rheumatology/ken398

Type

Journal article

Journal

Rheumatology (Oxford, England)

Publication Date

01/2009

Volume

48

Pages

32 - 38

Addresses

Kennedy Institute of Rheumatology, Imperial College London, London, UK. p.sumariwalla@imperial.ac.uk

Keywords

Synovial Membrane, Lymph Nodes, Monocytes, Cells, Cultured, Macrophages, Peritoneal, Animals, Mice, Inbred DBA, Humans, Mice, Arthritis, Experimental, Arthritis, Rheumatoid, Disease Progression, Lipopolysaccharides, Tumor Necrosis Factor-alpha, Immunosuppressive Agents, Drug Evaluation, Preclinical, Cell Proliferation, Dose-Response Relationship, Drug