Recent data suggest that ω-3 fatty acids may be effective in epilepsy, cardiovascular disorders, arthritis, and as mood stabilizers for bipolar disorder; however, the mechanism of action of these compounds is unknown. Based on earlier studies implicating ω-3 fatty acids as inhibitors of protein kinase C activity in intact cells, we hypothesized that ω-3 fatty acids may act through direct inhibition of second messenger-regulated kinases and sought to determine whether the ω-3 double bond might uniquely confer pharmacologic efficacy and potency for fatty acids of this type. In our studies we observed that ω-3 fatty acids inhibited the in vitro activities of cAMP-dependent protein kinase, protein kinase C, Ca²⁺/calmodulin-dependent protein kinase II, and the mitogen-activated protein kinase (MAPK). Our results with a series of long-chain fatty acid structural homologs suggest an important role for the ω-3 double bond in conferring inhibitory efficacy. To assess whether ω-3 fatty acids were capable of inhibiting protein kinases in living neurons, we evaluated their effect on signal transduction pathways in the hippocampus. We found that ω-3 fatty acids could prevent serotonin receptor-induced MAPK activation in hippocampal slice preparations. In addition, we evaluated the effect of ω-3 fatty acids on hippocampal long-term potentiation, a form of synaptic plasticity known to be dependent on protein kinase activation. We observed that ω-3 fatty acids blocked long-term potentiation induction without inhibiting basal synaptic transmission. Overall, our results from both in vitro and live cell preparations suggest that inhibition of second messenger-regulated protein kinases is one locus of action of ω-3 fatty acids.

Objective To investigate the association between weight or body mass index (BMI) and the development of hand osteoarthritis. Methods Systematic review of observational studies. Medical databases were searched up to April 2008. Articles that presented data on the association between weight and hand osteoarthritis were selected. The qualities of these studies were then assessed by two independent reviewers using a 19 criteria scoring system. Using the mean scores of all studies as a cut-off value, the studies were deemed as high or low quality. Study quality and study designs were combined to determine the level of evidence using best-evidence synthesis, which consisted of five levels of evidence. Results From the 25 studies included, two had cohort, three case–control and 20 cross-sectional study designs. Fifteen studies were considered high-quality studies. Of these high-quality studies, one cohort, two case–control and seven cross-sectional studies showed a positive association between weight or BMI and hand osteoarthritis. Based on three high-quality studies with preferred study designs (one cohort and two case–control) with a positive association, the level of evidence of the association between overweight and developing hand osteoarthritis is moderate. The approximate risk ratio of this association is 1.9. Conclusion Weight or BMI is associated with the development of hand osteoarthritis. The level of evidence of published studies is moderate according to best-evidence synthesis. Further high-quality cohort or case–control studies are needed to elucidate the role of weight in hand osteoarthritis.

The hallmark of fibrotic processes is an excessive accumulation of collagen. The deposited collagen shows an increase in pyridinoline cross-links, which are derived from hydroxylated lysine residues within the telopeptides. This change in cross-linking is related to irreversible accumulation of collagen in fibrotic tissues. The increase in pyridinoline cross-links is likely to be the result of increased activity of the enzyme responsible for the hydroxylation of the telopeptides (telopeptide lysyl hydroxylase, or TLH). Although the existence of TLH has been postulated, the gene encoding TLH has not been identified. By analyzing the genetic defect of Bruck syndrome, which is characterized by a pyridinoline deficiency in bone collagen, we found two missense mutations in exon 17 of PLOD2, thereby identifying PLOD2 as a putative TLH gene. Subsequently, we investigated fibroblasts derived from fibrotic skin of systemic sclerosis (SSc) patients and found that PLOD2 mRNA is highly increased indeed. Furthermore, increased pyridinoline cross-link levels were found in the matrix deposited by SSc fibroblasts, demonstrating a clear link between mRNA levels of the putative TLH gene (PLOD2) and the hydroxylation of lysine residues within the telopeptides. These data underscore the significance of PLOD2 in fibrotic processes.