Choline kinase inhibition in rheumatoid arthritis

Abstract

Objectives Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKα), 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. Methods Choline metabolic profile of FLS cells was determined by 1H magnetic resonance spectroscopy (1HMRS) under conditions of ChoKα inhibition. FLS function was evaluated using the ChoKα inhibitor MN58b (IC50=4.2 μM). 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. Results The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKα 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 ChoKα 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 ChoKα inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease. Conclusions These data suggest that ChoKα 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.

Metabolomics in rheumatic diseases: desperately seeking biomarkers

“…The choline pathway is highly active in FLSs 119 . Choline kinase-α (CK), the enzyme that catalyses the first step in the cytidine-diphosphate–choline pathway, is essential for phosphatidylcholine production.…”

“…In comparison with healthy tissue, elevated levels of CK have been associated with malignant transformation, invasion and metastasis in some human cancers 120–124 . CK is expressed in synovial tissue in RA and in cultured FLSs; furthermore, a CK inhibitor suppresses the aggressive properties of cultured RA FLSs, including cell migration and resistance to apoptosis 119 . In a serum-transfer model of arthritis, pharmacological CK inhibition (compared with vehicle-only) prevented development of arthritis when administered before serum transfer, and significantly decreased levels of markers of arthritis in treatment of established disease 119 .…”

GC/TOF-MS-based metabolomic profiling in cultured fibroblast-like synoviocytes from rheumatoid arthritis

“…The metabolomic approach enables the identification of changes in the metabolic pattern and the elucidation of variations in phenotypes imposed by perturbations such as gene modification or environmental stimuli [10,11]. Recently, metabolomics has been used to study the metabolic changes that occur in cancer cells and FLS obtained from Dupuytren's disease or RA [12][13][14][15]. Although the pathogenic behaviors of RA FLS have been studied extensively, the metabolic alterations of their transformed phenotype in RA remain to be elucidated.…”

Novel Therapeutic Targets in Rheumatoid Arthritis

“…As the synovium in RA shares similar characteristics with malignancies i.e. abundance of cytokines and oxygen radicals, it is tempting to speculate that choline kinase inhibition may control RA disease activity through suppression of the fibroblast-like synoviocytes (Guma et al 2015). This notion was supported by a murine study with an arthritis model which demonstrated decreased severity of arthritis with choline kinase inhibition (Guma et al 2015).…”