期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 74, 期 7, 页码 1399-1407出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2014-205696
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资金
- National Institutes of Arthritis and Musculoskeletal and Skin [1K08AR064834]
- National Institute of Allergy and Infectious Diseases [2R01AI070555]
- Ministerio de Economia y Competitividad [SAF2011-29699, RD12/0036/0019]
- National Institutes of Health [NCI P30 CA54174]
Objectives Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoK alpha), 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 H-1 magnetic resonance spectroscopy (1HMRS) under conditions of ChoK alpha inhibition. FLS function was evaluated using the ChoK alpha inhibitor MN58b (IC50=4.2 mu 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. 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 ChoK alpha 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 alpha 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 alpha inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease. Conclusions These data suggest that ChoK alpha 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.
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