Choline kinase inhibition in rheumatoid arthritis.

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 (1)H magnetic resonance spectroscopy ((1)HMRS) 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.

Symphyseal internal rod fixation versus standard plate fixation for open book pelvic ring injuries: a biomechanical study.

PURPOSE: This study investigates the biomechanical stability of a novel technique for symphyseal internal rod fixation (SYMFIX) using a multiaxial spinal screw-rod implant that allows for direct reduction and can be performed percutaneously and compares it to standard internal plate fixation of the symphysis. METHODS: Standard plate fixation (PLATE, n = 6) and the SYMFIX (n = 6) were tested on pelvic composite models with a simulated open book injury using a universal testing machine. On a previously described testing setup, 500 consecutive cyclic loadings were applied with sinusoidal resulting forces of 200 N. Displacement under loading was measured using an optoelectronic camera system and construct rigidity was calculated as a function of load and displacement. RESULTS: The rigidity of the PLATE construct was 122.8 N/mm (95 % CI: 110.7-134.8), rigidity of the SYMFIX construct 119.3 N/mm (95 % CI: 105.8-132.7). Displacement in the symphyseal area was mean 0.007 mm (95 % CI: 0.003-0.012) in the PLATE group and 0.021 mm (95 % CI: 0.011-0.031) in the SYMFIX group. Displacement in the sacroiliac joint area was mean 0.156 mm (95 % CI: 0.051-0.261) in the PLATE group and 0.120 mm (95 % CI: 0.039-0.201) in the SYMFIX group. CONCLUSIONS: In comparison to standard internal plate fixation for the stabilization of open book pelvic ring injuries, symphyseal internal rod fixation using a multiaxial spinal screw-rod implant in vitro shows a similar rigidity and comparable low degrees of displacement.