Targeting GM-CSF for collagenase-induced osteoarthritis pain and disease in mice.

OBJECTIVES: Pharmacological options for treating osteoarthritis (OA) are limited and alternative treatments are required. Given the clinical data indicating that granulocyte macrophage-colony stimulating factor (GM-CSF) may be a therapeutic target in human OA, we evaluated different treatment regimens with a neutralizing anti-GM-CSF monoclonal antibody (mAb) in an experimental OA model to determine their effectiveness on amelioration of pain and disease. METHODS: The collagenase-induced osteoarthritis (CiOA) model was induced in C57BL/6 mice, followed by different treatment regimens of anti-GM-CSF mAb or isotype control. Anti-CCL17 mAb treatment was also administered continually during the late stage of CiOA. Pain-related behavior (change in weight distribution of hind limbs), and disease (cartilage damage and osteophyte size) were assessed. RESULTS: Blocking GM-CSF only during early synovitis in CiOA prevented pain and disease development. Once OA pain was established, regardless of the treatment regimen, anti-GM-CSF mAb treatment rapidly and efficiently ameliorated it; however, unless the treatment was continued, pain returned and disease progressed. Continual late stage blockade of GM-CSF was able to ameliorate pain (between-group difference: -6.567; 95% confidence interval (CI): -10.12, -3.011) and suppress cartilage damage (P = 0.0317, 95% CI: -1.75, -0.0556). Continual late stage blockade of CCL17 showed similar effects on pain and disease development. CONCLUSIONS: Early and short-term GM-CSF neutralization is effective at preventing CiOA pain and disease development but, once pain is evident, continual GM-CSF blockade is required to prevent pain from returning and to suppress disease progression in mice. These data reinforce the potential benefits of anti-GM-CSF (and anti-CCL17) mAb therapy in OA and should inform further clinical trials.

Sodium monochloroacetate poisoning of greenfinches.

A large number of passerine birds, mainly greenfinches, were found dead or dying in a hedgerow close to a field of onions recently sprayed with sodium monochloroacetate (SMCA). An analytical method is described for isolating monochloroacetic acid from bird tissues, as its potassium salt, by ion exchange chromatography. The ion exchange eluate is evaporated to dryness, acidified, extracted with ether and the ethereal extract methylated with diazomethane. The concentration of the methyl ester of monochloroacetic acid is determined using the Mass Selective Detector in the selected ion mode. Chemical analysis confirmed the exposure of the birds to SMCA. It is calculated that 50 microliter of spray contained the lethal dose of SMCA for a greenfinch.

Effect of rendering procedures on the scrapie agent.

A pool of scrapie-infected sheep brains was used to spike mixtures of porcine bone and intestine. These were processed in pilot-scale facsimiles of 12 rendering procedures that were in use within the European Union in 1991, and three that were not. Meat and bone meal, and tallow, were produced from the rendered tissues. Suspensions of all the meat and bone meal samples, and two of the tallow samples were assayed in mice for scrapie infectivity. Neither of the tallow samples had any detectable infectivity but the meat and bone meal samples were positive, except for those produced by processes involving exposure to hyperbaric steam. In addition, greaves were produced from the scrapie-spiked raw materials by an atypical low-temperature process and subjected to solvent extraction with hot heptane. The treated greaves were then exposed to steam to drive off residual solvent. Although the starting titre of infectivity in these greaves was low, there appeared to be no reduction in infectivity as a result of the treatments with hot heptane and steam. However, there was no detectable infectivity in the meat and bone meal prepared from the greaves produced by the atypical low-temperature process after it had been exposed to hyperbaric steam.