Choline kinase inhibition in rheumatoid arthritis.

ABSTRACT: Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoK?), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage.Choline metabolic profile of FLS cells was determined by (1)H magnetic resonance spectroscopy ((1)HMRS) under conditions of ChoK? inhibition. FLS function was evaluated using the ChoK? inhibitor MN58b (IC??=4.2??M). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3?mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration.The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoK? expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoK? inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoK? inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease.These data suggest that ChoK? inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions.

SUBMITTER: Guma M 

PROVIDER: S-EPMC4382461 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature